Drug delivery particles and methods of treating particles to improve their drug delivery capabilities

ABSTRACT

A first embodiment of the invention provides a method of engineering changes in the morphological, chemical or physical features of a particle, to promote, for example, the formation of hairs and pores on the surface of the particle. The presence of these engineered features facilitating the delivery of agents to a target region, such as beclomethasone to the alveoli of the lungs. Although the particle acts to deliver desired agents to a target region, the particle itself may also be an agent. The invention also provides particles specifically engineered by the above method so as to produce carrier particles suitable for particular tasks.

FIELD OF THE INVENTION

The invention relates generally to the field of selectively modifyingthe morphological, physical and chemical features (architecturing) ofparticles to improve the delivery characteristics of the particles. Inparticular, the invention relates to the production and/or modificationof particles for delivery via inhalation.

BACKGROUND OF TE INVENTION

Drugs for treating respiratory and nasal disorders are frequentlyadministered through the mouth or nose as fine particles incorporatedinto a formulation. The particles between 1-5 μm are regarded asrespirable, i.e. capable of penetrating into the lungs. Particles fornasal delivery are generally, slightly larger (1-10 μm). Conventionaldry powder nasal formulations are often the same as, or are slightmodifications of inhalation formulations of the same drug. It is obviousthat there is an overlap in the particle size distribution, henceformulations intended for nasal delivery will contain particles lessthan 5 μm. Such standard nasal formulations are inefficient for a numberof reasons. Firstly, particles of 5-10 μm are more likely to deposit inthe nose, whereas, the particles below 5 μm are more likely to pass thenose and reach the pharynx, trachea and lung and are considered wasted.Because of the wastage, the portion of the drug remaining in the nose isinsufficient to treat the nasal condition, furthermore, the wastedparticles are likely to cause unwanted side effects due to theirdeposition beyond the nasal cavity. In a similar manner, deposition ofdrugs intended for the lungs in the oropharyngeal cavity may gain accessto the systemic circulation causing unwanted side effects. These twoexamples show the importance of controlling not only the particle sizebut also particle size distribution. Furthermore, it is also importantto control other particle morphological features (particle shape,particle density, surface texture of the particles to name a fewexamples) in order to ensure efficient therapy, while minimising anyunwanted side effects.

Techniques known in the art to obtain particles of 1-5 μm and 1-10 μmare milling, crystallisation, spray-drying and supercritical fluid toname a few common examples, however these techniques are fraught withproblems as briefly outlined below.

The milling process is undesirable for several reasons. It has thepotential to change more than the particle size of the feed material.The heat generated during milling reduces crystallinity and stabilityand causes chemical deposition of thermally labile molecules.Additionally, during micronisation brittle materials will tend tofracture during inter-particle collisions while ductile materials cannot be milled as they deform plastically rather than fracturin. Inaddition, the milled powder is highly cohesive and thus very difficultto mix due to poor and incomplete dispersion of agglomerates into theirsingle particles. Milling also generates a significant fraction ofunwanted under-size particles that must be removed for the reasonsoutlined above and are thus considered wasted making the milling processuneconomic. Additionally milling does not give the user control overparticle density, particle shape and particle surface texture.Furthermore, the milling process exposes the personnel to the hazardouseffect of the fine dust coupled with high product loss.

Particles of this size range (1-5 μm, 1-10 μm) are extremely difficultto achieve by crystallisation. The crystallisation process requiresconsiderable time and energy resources and defines such economicalissues as efficiency of solvent recycling, separation of waste(impurities) and consumption of raw materials. It is acknowledged thatminor changes in crystallisation conditions, for examplesupersaturation, temperature, impurity or cooling rate can producesignificant changes in the crystal and powder properties notably,particle size, shape, purity and defect structure followed by lesspronounced but significant variations in thermodynamic and mechanicalproperties. These effects have been recognised as the major batch tobatch and source variation problems leading to inconsistencies of thefinal product.

Spray drying has been seen as an alternative technique to micronisationas the shape of the particle is spherical and can be easily controlledwhilst producing particles with a narrow size distribution. However, thematerial formed contains various degrees of amorphous regions. Suchregions are often more sensitive to external conditions e.g. moisture,thus making the particles more susceptible to chemical degradation. Thistechnique is impracticable for heat-sensitive materials and suffers fromlow product yield. Furthermore, the particles produced are alwayscohesive and have poor flow and hence cannot be realisticallyaerosolised (Kawashima, Y et al., (1998), Effect of surface morphologyof carrier lactose on dry powder inhalation property of pranlukasthydrate, International Journal of Pharmaceutics, 172, 179-188).

Particles produced using supercritical fluids has been proposed asanother alternative technique to micronisation, unfortunately, thistechnique does not enable control over particle shape, particle densityand is unsuitable for large scale industrial production. In addition,supercritically processed particles are acicular (i.e. not spherical)and thus more difficult to mix, having prolonged mixing times due totheir tendency to agglomerate and segregate compared to sphericalparticles (rain, D. Pharmaceutical aspects of mixing solids, Pharm. J.1960, 185, 129-134). Additionally acicular particles have poor flowproperties (Staniforth, J. N., Powder Flow, In Pharmaceutics, TheScience of Dosage Form Design; Aulton, M. E., Ed; Churchill Livingstone;London, 1988; 600-628).

Important aspects in the use of small particles as obtained by the abovetechniques, for inhalation (for example), are their instability,cohesiveness and poor flow properties. Despite these aspects, particlesproduced by the above techniques are in reality currently used indifferent pharmaceutical areas to the detriment of the formulation andeffective drug delivery. This also severely limits the use of theseparticles, alone, or as carrier particles for inhalation.

In order to rectify one of the aspects as mentioned above, in this caseinstability, Patent WO 95/05805 describes the rearrangement andconditioning of fine-grained substance by treatment with a water vapourphase to produce a stable crystalline powder. Here, however, theparticle size and aerodynamic properties of the particles weremaintained as before conditioning. Thus, if the powder before treatmentcontains under-size particles the latter will still remain in the finaltreated product and this, as discussed previously, may causeside-effects. Despite ameliorating one of the above aspects, Patent WO95/05805 did not improve the aerodynamic properties, in particular theaerodynamic diameter of the particles.

The aerodynamic diameter is a major parameter dictating the depositionof inhaled particles in different regions of the airways. Theaerodynamic diameter is given by the equation:d _(a) =d _(g)(ρ_(p)/ρ₀χ)^(0.5)where d_(a) is aerodynamic diameter of the particle;

-   d_(g) is geometric diameter of the particle; ρ_(p) is the particle    density,-   ρ₀ is a reference density of 1 g/cm³; and χ is the dynamic shape    factor, which is 1 for a sphere.

It is evident from the above equation that there is a directrelationship between aerodynamic diameter and both particle density andparticle geometric diameter. For example, a perfectly spherical 10 μmparticle with a density of 1.5 g/cm³ has an aerodynamic diameter of12.25 μm. For the same perfectly spherical 10 μm particle whose densitywas reduced to 0.01 g/cm³ has an aerodynamic diameter of 1 μM. It isclear that d_(a) can be maintained or controlled by altering ρ_(p) oraltering d_(g) or altering both ρ_(p) and d_(g). From the literature, itis clear that particles with aerodynamic diameter >10 μm will not enterthe tracheobronchial tree, whilst particles with the same geometricdiameter and low particle density giving a low aerodynamic diameter (1μm) will not only penetrate the tracheobronchial tree, but also reachthe alveolar space (Sandra Suarez and Anthony. J. Hickey. 2000. DrugProperties Affecting Aerosol Behaviour. Respiratory Care, 45 (6)652-666).

It has also been shown that particles with small aerodynamic diameterare more attractive for inhalation therapy (Rita Vanbever, Jeffrey D.Mintzes, Jue Wang, Jacquelyn Nice, Donghao Chen, Richard Batycky, RobertLanger, and David A. Edwards. Formulation and physical characterisationof large porous particles for inhalation, Pharmaceutical research, vol.16, NO. 11, 1999), because they deposit in the alveoli space where thereis good contact with the blood stream. It is clear that the particlesconditioned described according to the process in WO 95/05805 are notoptimal for delivery to the lung as it did not bring any improvements inthe aerodynamic properties (i.e. there were no changes in both particlesize and particle density). It is crucial, for inhalation, that theaerodynamic properties should be improved in order to increase themedical value of inhaled drug particles.

Improvements have been obtained in drug delivery to the lower airways bylowering the density of the drug particles themselves, which in turnreduces the aerodynamic diameter, [See references: Edwards et al,Science, 276 (5320), 1868-1871, 199; Vanbever et al., 1999; Bosquillonet al, 2001; Ben-jebra et al 19991]. This reduction in aerodynamicdiameter enables easy aerosilization and dispersion within the airstream, thus allowing more drug particles to be become deposited in thelower airways. U.S. Pat. No. 6,284,282 discloses a process of applyingthe principle of producing larger particle of low density so as toachieve drug lung depositions in excess of 40% of the administered doseusing carrier/drug ratios of 10 to 1 w/w. This is strikingly superior tothe conventional formulations (i.e. carrier/micronised drug). Theengineered, low density drug particle of U.S. Pat. No. 6,284,282,aerosolize easily from the inhaler device; as a result less carrier isrequired. The improvements made come at a price in that typically 4-5%of the drug was included in a multi-component system. Such complexsystems increase the possibility of physical incompatibilities betweencomponents and may be undesirable in terms of patient acceptability. Inaddition, these complex systems will be slow release in nature as aresult of the use of polymeric matrix and lipid/waxy based excipients.This is unacceptable in treating acute respiratory conditions.Furthermore, the improved aerosolization is due to the larger size (i.e.larger d_(g)) which allows better flow of the powder. It would bedesirable to further reduce the aerodynamic diameter by producingsmaller particle size (i.e. reducing d_(g)) while maintaining good flowand hence aerosolization. Unfortunately reducing the particle size ofspray dried material (as used in U.S. Pat. No. 6,284,282) will causeincreased cohesion between particles drastically reducing the flowproperties of the resultant powder.

From the above, it is clear that improvements in the drug particleproperties improves overall drug deposition in the lungs. Current drypowder inhaler formulations (DPIs) use micronised drug particles,however, due to the high cohesion between drug-drug particles and poorflow properties coupled with the low therapeutic drug dose thus acarrier, usually lactose (whose particle size is greater than 60 μm), ismixed with micronised drug. The carrier particles have the followingthree roles for DPIs; acts as a bulking agent, improves the flowproperties of the formulation and hopefully allowing easy drugdetachment from its surface during inhalation.

All commercially available carriers present surface irregularities thatprevent drug detachment, upon inhalation, resulting in low depositionprofiles and batch-to-batch variations in drug deposition profiles isusual. Commercially available lactose carriers differ from each other(in terms of particle size, particle shape, particle density, particlesurface texture and polymorphic forms) depending on the source and themethod by which they were produced, which affect the deposition profileof the inhaled drug. Commercial batches of lactose obtained from thesame manufacturer, though possessing the same physico-chemical andtechnological characteristics, exhibited substantially differentbehaviours on inhalation, so that they could not be regarded asequivalent (Larhrib et al, 1999, The use of different grades of lactoseas a carrier for aerosolised salbutamol sulphate, Int. J. Pharm. 191,1-14).

Conventional formulations composed of a binary blend (micronised drug tocarrier, typically 1 to 67.5, w/w) only manage to achieve lung drugdepositions in the range of 15% of the administered dose, [See Shekunovand York, J. of Crystal Growth, 211(2000), 122-136, Lorgstrom, L.,Derom, E., Stahl, E., Wahlin-boll, E. and Pauwels, R., Am. J. Respir.Crit. Care Med, V61 153, pp 1636-1640, 1996]. A high ratio of carrier todrug is used in these current formulations not because of the diluentproperties of the carrier but because it has to be added in such largeconcentrations to improve the flow properties of the formulation.

It also follows that, since the drug is always generally mixed with acarrier and the carrier is present at a much higher concentration thanthe drug (1:67.5, w/w, drug:carrier, is common) in the formulation,improvements in the properties of the carrier should also improve drugdeposition.

Currently, carriers are obtained by crude, uncontrolled crystallisationfrom various solvents, with significant amounts of material and solventbeing wasted. After crystallization, the crystalline carrier isharvested, dried, sieved and comminuted if required. Due to the natureof manufacture the carrier tends to be dense and is of unpredictableshape and surface properties thus leading to batch-to-batch variationsin drug deposition. Such inconsistencies can be a burden when workingwith drugs that must be delivered in precise doses.

It is generally understood that the surface of the carrier particle hasareas of roughness (asperities and clefts). The site of an asperity orcleft is believed to be a region of high surface energy. It is thesesites, which the drug particles are attracted to, and adhere morestrongly to. Consequently, the detachment of drug particles from thesesites, upon inhalation, is reduced and uneven, ultimately resulting inunpredictable and reduced deposition of the aerosolised drug particlesinto the deep lung.

In view of the above problem, it is considered advantageous to reducethe number of these high energy sites available for the drug particle toadhere to. In U.S. Pat. No. 6,153,224, this was achieved by the additionof an anti-adherent material which reduced the adhesion between thecarrier and the drug. The respirable fraction of the drug actuallyachieved using the above composition was as high as 40% with lubricant,glidant or anti-adherent properties, dry mixed with the carrier, havebeen employed with the aim of reducing the forces of attraction betweendrug and carrier. Such lubricants are hydrophobic and toxic to thelungs.

Tee et al (1999, Proceedings of Drug delivery to the Lungs X, 33-361)described a process of adding fine particles first, to occupy the highenergy sites of the carrier, before the admixture of the drug, thisimproved drug deposition from 6.3% to 13.4%. Further, WO 95/11666,describes a process rather than physically adding the fine particles,these fine particles were produced in-situ using a milling process,preferably carried out in a ball mill, which alters the surfacecharacteristics of the carrier by removing asperities in the form ofsmall grains that in turn can become attached to the clefts of thesurface area of the particles, so saturating the high energy sites. As aresult of the preliminary treatment of the carrier, the micronized drugparticles are deposited preferentially on lower-energy sites and so aresubject to weaker forces of inter-particulate adhesion.

There are, however, disadvantages to such ternary mixes. Including thedifficulties of selecting an appropriate process of milling to generatethe necessary fine carrier, the type of fine carrier employed, and thesequence and time of mixing. All of which will have an impact on drugcontent uniformity and increase the complexity of the formulation. Internary mixes it is extremely difficult to know precisely how much fineparticles are needed, and the time during the mixing process when thelarge carrier particles become saturated with fine carrier. Any excessfine carrier for which there are no available sites on the large carrierparticles will cause saturation segregation. Displacement segregation,even in cases when an ordered ternary mix is obtained the differences inparticle size of carrier (very fine and coarse carrier) leads to furthersegregation and the formation of drug rich areas in the mix. (Travers,D. N., Mixing., In Pharmaceutics, The Science of Dosage Form Design;Aulton, M. E., Ed; Churchill Livingstone; London, 1988; 550-563).

U.S. Pat. No. 5,376,386 disclosed a process of producing smooth carrierparticles by crystallization from aqueous medium. The resultingparticles were found to improve drug deposition.

Further, the shape of the carrier was manipulated to form needles(Larhrib et al, 2000, Proceedings of Drug delivery to the Lungs XI,18-21). The engineered, elongated carrier particles, despite showingimprovements in Salbutamol sulphate deposition, from 5.5% to 22%, theformulations containing these elongated carrier particles produced lowerand inconsistent emissions of Salbutamol sulphate from the inhalerdevice. This was attributed to the poor flow properties of theengineered elongated carrier.

It is generally understood that in carrier/drug compositions, thecarrier is present in a much higher concentration than the drug. Thus,despite improvements made in the drug particle design, the overwhelmingpresence of the carrier will dilute and reduce the effect of theimprovements on overall drug delivery. However, by improving the carrierparticle design, thus reducing carrier/drug ratios, and promoting theaerosolization of the carrier and the drug particles, drug deposition inthe lungs will be increased. Despite this observation, efforts so far tomodify the carrier particles have not led to the kind of improvements indeposition obtained by the engineering of drug particles.

At present, conventional commercial carriers are designed to remain inthe inhaler device, remain in the mouth or impact at the back of thethroat as a result of their high density. However this does notguarantee drug detachment from the carrier nor drug dispersion intoprimary particles within the airstream. It is the strong adhesionbetween the drug and dense carrier resulting from the surface roughnessand/or presence of crevices on the surface of the carrier, that furtherimpedes drug detachment. In addition the fine carrier added as a ternarycomponent only has a static role, i.e. reducing the adhesion between thedrug and the coarse commercial carrier, drug detachment from the coarsecarrier is slightly improved but, again, It still does not guaranteedrug dispersion into primary particles within the airstream as a resultof the cohesiveness of such small drug particles. Thus increasing theamount of the drug particles impacting at the site at which the carrierimpacts. Assuming that the problems associated with adhesion andcohesion are alleviated, there are still major problems with the densityof the carrier itself. Thus the denser the carrier the more rapid it'simpaction caused by it's high inertia. The latter rapidly impactsleaving the drug insufficient time to dissociate from the dense carrierparticle. In addition the denser the carrier the greater the inspiratoryeffort required by the patient to aerosolise the formulation, dissociatethe drug from the carrier, disperse the drug into their primaryparticles in the airstream and entrain the drug particles into deeplung.

In view of the current understanding of the present technology field,there are thus two important issues that the Investigators focused onwhich can be taken from the teaching of the prior art:

-   1) The use of High density carrier-   2) Lowering the drug-carrier adhesion either by smoothing the    surface of the carrier or adding a static ternary component to the    formulation.

Apart from particle density and adhesive forces, there are otherimportant factors to consider, which are summarised in a review article(Venables, H. J. & Wells, J. L., Powder Mixing, Drug Dev. & Ind. Pharm,27(7), 599-612, 2001) highlighted the important factors of carrier anddrug particles in powder mixing, drug content uniformity,bioavailability and drug delivery. Some of these features, which includeparticle density ratios (between the drug particle and the carrierparticle) and particle surface texture, are briefly discussed below.

Effect of Particle Shape:

Spherical particles are easier to mix than any other shape. Acicular orflat plate particles prolong the mixing time due to aggregation.Spherical particles have optimal flow properties due to minimalinter-particulate contact and minimises segregation.

Effect of Particle Size:

A homogenous carrier particle size avoids segregation between componentsin powder formulation. A small particle size and narrow sizedistribution are required to improve drug bioavailability, however, suchsmall particles give rise to flow problems and segregation caused by thepresence of fine particles within the mix. Larger particles act assieves through which the smaller particles percolate. Matching theparticle size of the carrier to drug will improve mixing, contentuniformity and reduce segregation. From Zimon's re-suspension model,where it is assumed that the drug slides laterally along the surface ofthe carrier particle, before it falls off. The longer the drug particlehas to travel across the surface of the carrier particle, the greater isthe drag force needed to overcome adhesion and friction between drugparticle and carrier particle surface (Zimon, A. D., 1982. Adhesion ofDust and Powder, 2^(nd) edn. Consultants Bureau, New York, pp. 307-319).From this, it is understood that small and or spherical particles mightbe ideal for re-suspension of drug particles.

The size of the particles is a critical factor affecting the site oftheir deposition, since it determines operating mechanisms and extent ofpenetration into the lungs. Thus aerosol particles >100 μm generally donot enter the respiratory tract and are trapped in the naso/orpharynx.Particles >10 μm will not penetrate the tracheobronchial tree. Particlesmust generally be <5 μm in order to reach the alveolar space. On theother hand, particles <0.5 μm in diameter penetrate the lung deeply, buthave a high tendency to be exhaled without deposition. However, somestudies have found that breath-holding can minimise expiration of smallparticles (Sandra Suarez and Anthony. J. Hickey. 2000. Drug PropertiesAffecting Aerosol Behaviour. Respiratory Care, 45 (6) 652-666). Infants,young children, the elderly and patients in acute distress may not beable to hold their breath effectively, even after proper instruction andhence they do not benefit from the pharmacological effect of these fineparticles. These fine particles <0.5 μm are pharmacologicallyadvantageous as they penetrate deep into the lungs, tend to be larger innumber than larger particles and have high specific surface area thatwould enable fast and complete drug absorption. Unfortunately these fineparticles are generally cleared by exhalation, mucociliary clearance,ingestion and digestion by alveolar microphages. Thus, it is desirableto develop formulations, whereby, such small particles can be maintainedin deep lung without discomforting the patient, without being exhaledand without being phagocytosed.

Particle Density:

Various problems can arise when density differences exist between thecomponents of a mix such as increased mixing time coupled with increasedpropensity for segregation. Gravitational forces pull the denserparticles (i.e. carrier) to the bottom, leaving the less dense particles(i.e. drug) on top, in addition vibration will enhance segregation. Forthe inhalation scenario low density particles are preferred, it is alsofurther preferred that the components of the formulations are of matcheddensities (i.e. drug and carrier). The latter improves mixing andreduces segregation caused by density differences between the componentsof the formulation.

Particle Surface Texture:

Porous or rough surfaced particles are suitable for stabilising the mixand ensure uniform drug content uniformity. In the inhalation fieldporous particles are more suitable than non porous particles of the samesize as they have a smaller aerodynamic diameter. The surface nature ofthe components of the formulation need also to be considered for exampletheir hydrophilic and hydrophobic nature. It has been shown that thedeposition of Beclomethasone [a hydrophobic drug] from lactose carrierwas dramatically increased when the lactose particles were pre-coatedwith magnesium stearate [a hydrophobic lubricant] Latent WO 01/05429A2). In this instance a hydrophobic-hydrophobic surface nature improvedthe deposition of the drug. The hydrophobic and or hydrophilic nature ofthe drug and or carrier affects the ease of mixing, stability of the mixand content uniformity.

Ordered Mixing:

The attainment of an ordered mix (i.e. the drug is dispersed on thesurface of the carrier) is important in that it prevents segregation ofpowder mixes. Adhesional forces facilitate the attainment of orderedmixes, in cases where the carrier-drug adhesional force cannot over-comedrug-drug cohesive force, or where the carrier particle is extremelysmall (and milling cannot produce drug particles smaller than thecarrier), or where the dose of the drug is very small coating processesare alternatives to producing ordered, uniform and stable mixes.

Drug Concentration:

The drug content variation in a mix increases as the drug content isreduced (as in the case with highly potent drugs), and in suchcircumstances it is virtually impossible to achieve blend uniformitywith a low-dose drug. High particle population is required for low-dosedrugs, therefore, particle size control and milling (particle sizereduction) are extremely important. However, milling increases cohesionbetween drug particles, and the agglomerates produced must bedeaggregated.

At present, the level of drug deposition possible using a compositioncomprising a carrier and a drug is limited and can be improved slightlyby the engineering of the drug particles, the carrier particles, orboth. In view of the limited success achieved so far there is a need forimproved engineering of the drug, carrier or both particles.

In order to produce suitable particles there is a need for a method oftreating particles in a controlled manner so as to produce particleswith the right physical, morphological and/or chemical characteristics,for the drug or carrier with which it is to be associated.

An ideal particle for inhalation or nasal delivery (or in fact anypharmaceutical application) should not have the draw-backs detailedabove. An ideal particle should have: suitable adjustable and controlledsize range in order to target the particles to the desired region;suitable and controlled aerodynamic diameter (this encompasses particledensity, particle size); suitable and controlled particle surfacetexture; suitable and controlled shape; a narrow size distribution; acrystalline nature; a physical and chemical stability; the capacity forinstantaneous and modified release; the ability to allow easy mixingwith any other component; the capability of being manufactured on anindustrial scale; the capability of comprising up to 100% puresubstance; the ability of being free flowing irrespective of theparticle size; the capability of being aerosolised on it's own or with acarrier (wherein the aerosolisation is device independent andaerosolised with minimum inhalation effort), a simple and reproduciblemethod of production.

Furthermore the ideal carrier should: be independent of the nature ofthe drug (i.e. hydrophobic or hydrophilic); not require any furthercomponents apart from the drug; stabilise the mix; be versatile (i.e.,it is able improve the formulation in which it is included for exampleimproving mixing, improving tabletting properties, improvingdisintegration time, good diluent, etc . . . ). Adhesion and/orcohesion, which are common problems in dry powder inhalation aerosols,are of less importance or irrelevant in the case of an ideal carrier.The carrier should have good loading capabilities arising partly fromit's great specific surface area, thus more drug can be loaded usingsmall amount of the carrier, thus minimising the cost and minimisingunwanted side effects. The carrier should help the drug to reach thedesired site of action.

The advantage of the present invention is that it gives the user controlover one or more of the physical, morphological and/or chemicalcharacteristics needed to obtain a more ideal drug or carrier particle.

SUMMARY OF THE INVENTION

This invention relates to a new process of creating hairs (projections),pores and controlling the growth of hairs, pores, the particles, changesin physico-chemical properties and their combinations, i.e.architecturing particles.

Accordingly, one aspect of the present invention provides a particle,having at least one changed morphological, chemical or physical feature,wherein said changed feature facilitates the attachment of at least oneagent to the outer surface of the particle, thus permitting the particleto act as a carrier for said at least one agent.

Preferably, one of the changed (or engineered) features is either ahair, a pore, a changed hollow volume or an altered particle size. Byaltering such features various particle characteristics can becontrolled, such as altered particle density, altered aerodynamicdiameter, altered surface texture, improved flow properties, surfacerestructuring to reduce cohesiveness.

It will be appreciated that the term hair, within the scope of thepresent invention, is intended to include any projection from thesurface of a particle. Further preferably such hairs may be between0.001 and 5000 micrometres in length.

Important physico-chemical properties of the hairs, which can beaffected to increase the usefulness of the particles, include the type,nature of the agent(s) of which they are composed and the number,surface density, direction of growth and the rate of growth.

There is no restriction on the type of material forming hairs, enablinginstantaneous, controlled or sustained release profiles, in order tosuit the intended use. The hairs can be produced from a suitable andsafe (generally recognised as safe “GRAS”) penetrating enhancer agent toachieve the intended pharmacological effect of the therapeutic agent.

The nature, quantity, the length and the physico-chemical properties ofthe hairs can be engineered in a controlled fashion to suit the intendeduse, to give for example increasing specific surface area, thus moretherapeutic agent can be loaded onto the hairs reducing the quantity ofcarrier required compared to the conventional carrier used in thecurrent dry powder inhalation aerosol.

The present invention is contrary to the general trend of the prior art,where rough surfaces have been seen as a burden for traditional drypowder inhalation, such rough surfaces in this invention areadvantageous (see below). In fact the present invention seeks to promoteroughness of the particle surface (or asperities) by the presence ofprojections (hairs) and/or pores.

The presence of hairs maintain the stability and content uniformity ofthe mix. The hairs also minimise the contact between the carrierparticle core and the therapeutic agent. The hairs are part of thecarrier, however, they act as a ternary component minimising fullcontact between the carrier core and the therapeutic agent. This is anew concept contrary to the prior art, where a ternary component (suchas fine carrier) is added as a static component only to reduce theadhesion between the therapeutic agent and carrier. The density of thehairs can be adjusted to enable the hairs to oscillate or vibrate (inthis instance hairs acts as a dynamic ternary component, which iscontrary to the prior art when the standard ternary components isstatic) when the particles are subjected to inhalation. Low adhesion oftherapeutic agent particles to the hairs combined with efficientoscillation of the hairs allow better detachment of the therapeuticagent particles, the remaining therapeutic agent particles attached tothe hairs and/or to the carrier core will travel with the low densitycarrier. The increased surface area conferred to the particle by hairsautomatically improve aerodynamic properties of the particle, in thatthe inhalation air flow acts on this surface area to propel and suspendthe particle in the airstream. Hence, the greater the surface area ofthe particle the greater the propulsion and suspension of the particle.

Furthermore, the hairs can be produced from a bioadhesive agent which atthe point of carrier impaction allow the hairs to act as grappling hooksanchoring the carrier-therapeutic agent particles or therapeutic agentparticles to the impact site of the lung epithelia allowing thetherapeutic agent to be released and absorbed. This concept is importantfor delivering very small particles below 0.5 micrometers such asliposomes to the lung, this particle size range is known to be clearedfrom the lung, whereas the presence of hairs will maintain them at theimpact site until they have released their therapeutic agent pay load.Hence the presence of hairs will maintain particles lower than 0.5micrometers at the impaction site, preventing their expiration,muco-cilliary clearance or ingestion and digestion by macrophages. Suchsmall particles are pharmacologically advantageous as their largesurface area to volume ratio give superior and faster absorption. Thehairs increase the residence time of the particles by maintaining theparticles at the impact site. Thus the therapeutic agent concentrationat the site of action is higher and this is appropriate for a locallyacting therapeutic agents where biological activity is dependent ontherapeutic concentration at the site of action. These small size rangesare thus made pharmacologically useful with this technology whilst intraditional formulations these size ranges are usually cleared from thelungs and are consequently of no therapeutic or economic value due totheir wastage.

Preferably, the particle of the present invention will have a lowdensity and have hairs on the surface of the particles.

Preferably the density of the particle may be reduced by increasing thehollow volume of the particles.

Advantageously, the particles may be spherical in shape. This regularshape coupled with low density of the carrier allow better technicalhandling and easier and total aerosolisation of the powder. When theparticles are used in dry powder inhalation, the regular sphericalshaped particles flow better allowing consistent filling and betteremptying during inhalation.

The preferred particle size is between 0.05 μm and 4000 μm in diameter.

According to the present invention the lower density of the carrierparticle, the spherical shape of the particle together with the presenceof hairs on the particle surface, improved the aerodynamic properties ofthe particles, facilitating their easy aerosolization from a dry powderinhaler device (and the emitted particles will travel further in the airstream despite changes in air stream velocity).

The low density of the carrier facilitates a long flight time which inturn allows more therapeutic agent particles to detach, oscillation ofthe hairs promotes further detachment of therapeutic agent particlesfrom the carrier whilst those therapeutic agents particles which do notdetach from the carrier particles are carried to deep lung to the impactsite of the light, low density carrier particle. The bioadhesive andanchoring functions of the hairs retain the therapeutic agent at thelung epithelia for sufficient time to enable therapeutic agent transferto the lungs. The carrier particle of the current invention deliversmore therapeutic agent to the site of action compared with thetraditional high density carrier, that usually remains in the inhalerdevice or impacts in the mouth.

Advantageously, the engineered carrier may be composed of 100%therapeutic agent, thus allowing the therapeutic agent to be deliveredon its own or act as a carrier for one or more therapeutic agentparticles The carried therapeutic agent particles can be traditionallyprepared or engineered according to the current invention.

When a potent therapeutic agent is used in a mix, the amount oftherapeutic agent used is small and to ensure a uniform mixture it isnecessary to increase the number of therapeutic agent particles persample or dose. To do this it is necessary to use a smaller therapeuticagent particle size, however, producing such very fine powder isdifficult and often attended by severe aggregation (using conventionalmilling, spray drying or crystallisation techniques) thus defeating theobject of size reduction in the mixing process. When the proportion oftherapeutic agent is extremely small and finally presented in a smalldose unit, physical dry mixing of solids will fail to produce anadequate dispersion of therapeutic agent within the formulation. Toavoid the above drawbacks, the current invention adopts an efficient andreproducible strategy in which the therapeutic agent is maintained in aliquid. The resulting therapeutic agent-liquid mix is reduced in size byatomisation to form a fine mist. This fine mist contains individualliquid droplets whose size is much smaller than that obtainable byconventional milling such as micronisation and spray-drying. Furthermorethese liquid droplets are uniform in size and therapeutic agent content.Using the right atomisation protocols, the size of the liquid dropletscan be arranged to be several orders of magnitude smaller than that ofcarrier particle with which it is mixed. Mixing of the liquid dropletsand carrier results in an efficient, uniform and stable mix. Thetherapeutic agent adhered to the particle is uniformly distributed andsmaller in size than the carrier. The therapeutic agent particles canconsequently travel with the low density engineered carrier to the deeplung. The small size of the therapeutic agent particle enables fastdissolution and transport in lung epithelia. Hence, the problems ofadhesion and cohesion encountered in traditional dry powder inhalers isof no consequence with this invention which is in direct contradictionto the current state of the art.

Advantageously, one or more agents (one or more of which may betherapeutic), carried in a liquid or vapour-loaded state can betransferred to the particle. This liquid state, vapour-loaded state andtransferred agent corrects surface defects, restructures the surface ofthe particles which in turn reduces the cohesiveness of the particles,alters the particle density, particle size and thus their flowproperties. The transferred agent is uniformly distributed to theparticles forming a stable and homogeneous mix. The preferredvapour-loaded states for small quantities of agent transfer includemist, droplets, foam, spray, steam, fog or vapour. The vapour-loadedtransferred state is more efficient and effective than conventionalmethods of mixing dry micronised powders.

Further the particles adhered to the carrier can be present on thecarrier as discrete, discontinuous or continuous particles or films.Apart from transferring agent particles to the carrier, the method oftransfer using the current invention can be manipulated to also changeat least one or combinations of one or more morphological, chemical orphysical features of the particle and/or, transferred agent accordingthe above. In addition the change of at least one or combinations of oneor more morphological, chemical or physical features of the particle canbe manipulated to occur before, during or after the transfer of theagent.

According to the present invention an agent can be selected that impartsto the resulting particles a plastic nature, as it is known thatmaterials that are plastic in nature deform plastically (with thepossibility of shape change) rather than fracturing or elasticallydeforming. The majority of therapeutic agents used in pharmaceuticalstend to have elastic or brittle (i.e. fragmenting) behaviour. Particlesintended for deep lung administration may be preferred to have aplastically deforming component as such these particles absorb andtransfer the energy of impact to plastic deformation preventing bouncingof the particles from the site of impact in the lungs. This plasticdeformation may also lead to a change in shape of the particle furtherincreasing the contact area between the particle and the lung at thesite of impaction thus increasing the drug absorption. This phenomena isextremely important for fine powder (i.e. particles less than 1micrometer), even though they penetrate deeply into the lung, they areexhaled partly because these particles have bounced off the surface ofthe lung epithelia. Thus giving the particles a plastic behaviour willprevent bouncing of the particle, instead keeping them at the impactsite thereby maximising therapeutic and minimising wastage and unwantedside-effects. Furthermore, the plastic nature of these particles aremore stable during processing, packaging and shipping as they aremechanically tough and are less likely to abrade than material that arebrittle in nature. Examples of agents that impart a plastic nature tothe particles are Polyvinyl alcohol, Polyvinylpyrrolidone andpolyethylene glycol (PEG).

According to the present invention the selected agent may impart to theparticle a brittle nature such that when these particles impact in deeplung the particle fragment into smaller particulates, these smallerparticulates are then spread over a larger area compared to the initialimpact site thus increasing drug absorption. In the present inventionthe brittle behaviour of lactose was enhanced by forming very fine andweak projections. These projections upon impact fragment givingultra-fine powder that increases the surface area of contact betweenthese particles and the lung.

Another aspect of the present invention provides a method of producingengineered articles for use alone or as carriers for one or more agents,comprising the steps of:

-   a) processing at least one agent to form a particle;-   b) treating by making available a fluid alone or in combination with    at least one additive to the particle to promote changes in one or    more of the morphological, chemical or physical features of the    particle;-   c) repeating steps (a) to (b) as many times as necessary;-   d) harvesting engineered particles;-   e) repeating steps (a) to (d) as many times as necessary.

The present invention provide specific examples, numbered 1 to 18, ofengineering treatments which produce engineered particles for use asagent carriers substantially as described herein with reference to theexamples.

The severity of the treatment conditions and the time of treatmentdetermines the extent and the degree to which there are changes in theparticles morphological, chemical or physical features. The severity ofthe treatment conditions are controlled at least by the time oftreatment, state of matter in which the particle meets the state ofmatter of the fluid and the addition of an agent or additive.

Preferably, the promoted change of step (b) results in at least onechange to the particle from a list consisting of but not limited to:promoting the growth of hairs; modifying the properties of the existinghairs; promoting the formation of pores; modifying the properties ofexisting pores; and increasing the hollow volume of the particle.

Preferably the fluid used in the above method contains at least onemedium that promotes changes in any of the morphological, chemical orphysical features of the particle and/or aiding the transfer of an agentto the particle. Further preferably the fluid is either aqueous,organic, or a combination thereof. It is also preferable that the fluidcomprises either water, acetone, ethanol, or combinations thereof.

Preferably during the step of treating the particle with fluid, thefluid is introduced to the particle either in bulk, as droplets, as afoam, as a mist, as a vapour, as steam or combination thereof. Theparticles and fluid can be static or in motion or combinations thereof.

Alternatively, during the step of treating the particle with fluid, theparticle is introduced to the fluid either in bulk, as droplets, as amist spray, as a vapour or as a steam or combinations thereof. Theparticles and fluid can be static or in motion or combinations thereof.

It is appreciated that it may be advantageous if at least one furtheragent is added to the fluid before and/or during and/or after theparticle has been treated with the fluid.

Suitable states of matter for the particle and fluid include: solid,frozen, liquid, gas (ideal, real or mixtures thereof), vapour,supercritical fluids, solutions, suspensions, dispersions, emulsions ormicro-emulsion, colloids, liquid crystals, visco-elastic, gels, slurry,paste, semi-solid, molten or combinations thereof.

In the above method additives are introduced to facilitate the particleengineering process. Such additives can be environmental ornon-environmental. Preferable environmental additives include: heat,moisture, vacuum, radiation, pressure, shear forces, magnetic forces,vibration, stirring, vortexing, mixing, tumbling, centrifuging,masticating, ultra-sound waves or extruding, electrical, or combinationsthereof.

Further preferably, at least one selected additive in the aboveinvention is stirring. Another preferable additive in the above methodis the maintenance of heat in the range −200 to 200° C.

Agents can be used to facilitate the particle engineering process, suchagents are preferably polymers. Preferably such polymers arebiodegradable or erodible. Further preferably, suitable polymers areselected from a group consisting of polyvinyl alcohol,polyvinylpyrolidone and polyethylene glycols.

In the above method, the step of treating may preferably last forbetween 1 microsecond and 30 minutes.

The method of the present invention maintains the particle shape whilstadjusting the particle size distribution to the desired particle sizerange. This can be easily achieved without changing the operatingparameters used to produce the untreated original particles.

It is appreciated that the particles of the present invention may beused to deliver therapeutic agents via a range of routes, such routespreferably include: pulmonary, oral, parental, nasal, rectal, tonsillar,buccal, intra-ocular, topical/transdermal, or vaginal.

The respiratory anatomy has evolved in such a way as to actively preventinhalation of airborne particulates. The upper airways (nose, mouth,larynx and pharynx) and the branching anatomy of the tracheobronchialtree acts as a series of filters for inhaled particles. Thusparticles >100 micrometer generally do not enter the respiratory tractand are trapped in the naso/oropharynx. Particles greater then 10micrometer will not penetrate the trancheobronchial tree. Particles mustgenerally be <5 micrometers in order to reach the alveolar space“(Suarez S. and Hickey. A. J 2000. Drug Properties Affecting AerosolBehaviour. Respiratory Care, 45 (6) 652-666). This current inventionenables control of particle size, particle density and particle surfacetexture in order to control the aerodynamic properties of the particle,and from the above, such resultant particle(s) can be used tospecifically target a particular region of the respiratory tract. Withthe current invention, particles targeting multiple sites of therespiratory tract may be formulated together to enable all the sites tobe targeted at once or formulated individually to target only one regionof the respiratory tract. The particles designed for a targeted regioncan be used as carrier for particles designed to target a regiondifferent from the carrier.

The method of the present invention enables control of the changes inmorphological, chemical or physical features whilst transferring anagent to the particles at the same time.

The particles of the present invention are advantageously used todeliver any of the agents selected from a group comprising: therapeuticagents, prophylactic agents, diagnostic agents, excipients, diluents,flavourants, fragrances, dyes, nutrients, sweeteners, polymeric drugs,proteins, lipids, organic substances, inorganic substances, pro-drugs,antigens, and combinations thereof.

Preferable therapeutically active agents include: corticosteroids,antiinflammatories, antitussives, bronchodilators, diuretics,anticholinergics, hormones, analgesics, vaginal preparations,antiallergics, anti-infectives, antihistamines, anti-neoplastic agents,anti-tuberculous agents, therapeutic proteins, and peptides andderivatives thereof.

A further embodiment of the present invention provided a low densitycarrier particle having hairs on the surface thereof, wherein theparticle acts as a carrier for the delivery of agents that are eitheranti-inflammatory drugs, bronchodilator drugs or a combinations thereofinto the lungs of a patient via dry powder inhalation.

It is appreciated that in some circumstances it may be advantageous forthe particle itself to be a therapeutic agent. Therefore, the principlesapplied to produce the carrier particle can also be applied to produceparticles of the therapeutic agent so that these therapeutic agentparticles, can advantageously, be delivered on its own or combined withone or more carriers. The latter carrier can be conventionally preparedcarrier or carriers prepared according to the present invention orconventionally prepared therapeutic agent or therapeutic agents preparedaccording to the present invention.

Fluticasone propionate, beclomethasone dipropionate and salbutamolsulphate and combinations thereof are a selection of therapeutic agentsthat can be advantageously delivered using the hairy, low density andporous, particles of the present invention.

Preferably, where the method includes the set of adding a further agentto the fluid/particle mix during the treatment of the particles suchagent is beclomethasone, fluticasone or salbutamol sulphate.

Of the above agents, combinations of beclomethasone and lactose,fluticasone and lactose, polyvinyl alcohol and lactose, orpolyvinylpyrolidone and lactose, or even lactose on its own, areconsidered most preferable.

The morphological features of the architectured particles are assetsthat enable, for example, the entrapment and increasing the shelf-lifeof perfumes, flavourings, and taste-masking agents.

Hairs can be surfactants retarding drug creaming from suspension,enhance solubility in certain media, lubricate the valve and it'scomponents during the depression and release cycle associated withcontainer emptying of Metered Dose Inhalers, stabilising the suspension,minimising friction between particles, minimising drug particle adhesionto container walls, dispersing particles within the medium, preventcaking and maintain a homogenous drug particle size.

This technology has great applicability in other areas, for brevity,such examples are nasal delivery, tablet formation technology, deliveryof controlled systems such as liposomes. This invention, from aknowledge of the route and site of delivery for the agent, knowing therequirements for that route of delivery and the physico-chemicalproperties of the agent to be delivered, thus, this invention bringssolutions for designing suitable particles required for that route andsite of delivery.

Patent WO 00/27373 highlighted the important properties of particles fornasal delivery. In the latter patent, 85% of the therapeutic agentsparticles to be delivered have a size over 5 μm and at least 90% have asize less than 20 μm, and when mixed with an excipient 90% of theparticles are of a size less than 10 μm. The particles of the presentinvention fulfil this criteria and are thus applicable for nasaldelivery. Furthermore, the particles of the present invention can beengineered to include a mucoadhesive penetrating enhancer component thatmaintain the particles at the site of action without being cleared fromthe nose and promote absorption and transportation through the nasalmucosa. Particles for nasal mucosa should not be smooth as suchparticles may bounce off the nasal mucosa, whilst particles withprojections, such as described in this patent will anchor onto the nasalmucosa and by virtue of the mucoadhesive incorporated within theparticles and this will keep the particles in contact with the nasalmucosa. Particles with projections will be retained also by the nasalhairs further increasing the deposition of therapeutic agent to thenasal mucosa.

In tabletting technology it is well known that optimal tablets areobtained when plastically deforming and fragmenting materials arecompacted together. The plastically deforming and fragmenting materialare usually prepared as a physical mixture, to this physical mixture thedrug is added before tabletting. However, in this instance a uniformformulation cannot be assured and de-mixing and segregation alwaysoccurs. The particles of the present invention can be successfully usedin tabletting as the plastically deforming PVP, fragmenting lactose anddrug are incorporated into one particle, assuring formulation uniformityhence better compressibility than physical mixtures, minimising theprocessing time, minimising the cost compared to labour and costintensive wet and dry granulation techniques routinely used in tablettechnology. Furthermore, the particles of the present invention arespherical, hence they flow better from the hopper into the die and packeasily. In addition, their hollow nature (less resistive to thecompression force) enabling the particle to collapse under low pressureso that the fragmenting and plastic-deforming components come into playat an earlier stage of the compression cycle. Since low compressionforces are commonly employed for the particles of this invention, thereis increased longevity of the tabletting machine and tooling.Furthermore, the resulting tablets are less friable and disintegratefaster which are both desirable properties in tablet manufacture.

The particles of the current invention can be advantageously formulatedin a suspension, this suspension can be used for example in oral dosageforms, topical dosage forms, parenteral dosage forms and the like. Theparticle as shown in the examples and detailed description, are below 5micrometers to ensure a slow rate of sedimentation of the suspendedparticles. The engineering process allows the density of the particle tobe matched with that of the dispersing medium. The particles areisometrical in shape and of narrow size distribution allowing theparticles to settle at similar velocities in the dispersing medium toprevent phase separation of the particles and the dispersing medium.Further the engineered pores of the particles allow the flow of thedispersing medium into and around the particles. The flow of dispersingmedium into the hollow volume of the particles not only minimises thedensity differences between the particle and the dispersing medium butit help support, suspend and maintain the particle in the dispersingmedium thereby sedimentation of the particles within the dispersingmedium is reduced.

Liposomes or nano-particles are usually made from waxy materials such assurfactants and are consequently delivered by wet nebulisation but neverby dry powder aerosolisation using conventional technologies. This isdue to the high liposome-liposome (or nano-particle-nano-particle)cohesion and adhesion forces. However, these high adhesive forces areunimportant with the method of engineering particles of the presentinvention (i.e. light hairy carrier particle and liposome or light hairycarrier and nanoparticle) and deep delivery of drugs into the lungs ismade possible. Liposomes are ideal carrier systems in that they arehydrophobic, which will be quickly and easily absorbed and transportedby the hydrophobic lung epithelia. Liposomes, generally, are usuallyopsonised or phagocytised hence they have a short biological half-life.Application of this process to produce hairs on the surface of liposomesincreases their biological half lives and hence improves theirpharmacological usefulness.

Previously, it was stated that the carrier could be designed withmorphological features which actively promote drug detachment from thecarrier. One such morphological feature has been commented in U.S. Pat.No. 5,869,098, however, the author's failed to realise its importance.It was used in this patent purely as a reference to indicate thecessation of crystallization. However this invention is specific inactively seeking to produce this feature as one of the important part ofthe engineered particles. This feature as described, U.S. Pat. No.5,869,098 is “fine cat whisker-like needles and tiny blades which growand project along the surface”.

Although the present invention, which comprises a multitude oftechniques, shares one technique, that is immersion of solids insolvents, with U.S. Pat. No. 5,869,098, the aim and resultant product iscompletely different and possess several advantages compared to U.S.Pat. No. 5,869,098.

The principle events in U.S. Pat. No. 5,869,098 are:

-   1 production of floss using high temperature and high shear forces;-   2 Chopping of the floss;-   3 Addition of additive, which may be bioactive that may act as a    nucleating agent;-   4 Immersion or addition of organic solvent (with or without the    presence of water), or subjection of the floss to organic solvent    vapour, with the intention of producing a crystalline material;-   5 The final recovered product is in the form of spheroidal    micro-crystallites that essentially consist of agglomerated rods in    the form of a “dome or raspberry like structure”;-   6 The product is aimed as a fondant comestible;-   7 Suggest the use of the resultant particles as inhalants.

For the present invention, addressing items 1-7 above. A floss is notproduced, in fact the starting material need not even be processed butcan be used in the raw state. Contrary to U.S. Pat. No. 5,869,098, thestaring material for this invention is not limited to those that areamorphous, crystalline materials can also be processed with the sameresults. There is also no limitation on the starting shape or size. Thefloss is amorphous in nature and consequently is thermodynamicallyunstable hence it was necessary to process it at comparatively lowtemperatures otherwise it's structural integrity was destroyed.

Processing the floss at elevated temperature will ultimately lead touncontrollable crystallization and floss destruction. Whereas, in thispresent invention the application of heat is desirable, in that itreduced the processing time, it facilitated pore and hair formingprocesses whilst increasing internal hollow volume and pore size. Inaddition the solid nature of the starting material is more resistant toelevated temperatures compared to the floss and the elevated temperatureenabled the starting material to grow in an isometric manner, whilstmaintaining it's high degree of mono-dispersity and maintaining theshape of the original particle.

Since the floss is made from sugars, this limits the starting materialsto sugars. The spheriodal micro-crystallites of U.S. Pat. No. 5,869,098are not true spheres but agglomerates of rod like crystals. Whereas, inthe present invention the particles retain the original shape of thestarting material. Since the final product of U.S. Pat. No. 5,869,098 ismuch denser than the starting floss these particles may be undesirablefor inhalation as light particles are required (as discussed above). Inaddition for inhalation, these micro-crystallites must disperse in theinhaler device and given the fact that this dispersion occurs insaturated sugar solutions, this would be difficult to obtain in aninhaler device in the dry state. Furthermore the rough surfacecharacteristics of the micro-crystallites would impede drug detachment.All of these limit the use of such particles in dry powder inhalerdevices. The present invention produces aerodynamically favourableparticles with low bulk density that can be delivered as a whole to deeplung rather or as fragments. In addition the present invention candeliver the drug alone without the need of a carrier, whilst U.S. Pat.No. 5,869,098 needs re-crystallised floss as carrier.

U.S. Pat. No. 5,869,098 whilst re-crystallising amorphous materialincreases it's bulk density and lowers the corresponding specificsurface area. In contrast, the present invention increases the specificsurface area and decreases the bulk density. Also in the presentinvention the number, size the density and other characteristics of thehairs can be manipulated to achieve the requirements for thatapplication.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which show various preferred embodiments of theinvention:

FIG. 1 shows a scanning electron micrograph of Spray-dried lactoseparticles (before treatment with ethanol);

FIG. 2 shows a scanning electron micrograph of lactose particles of FIG.1 after exposure to hot ethanol (45° C.) for 10 min;

FIG. 2.1 shows a photograph of a fruiting head of dandelion fluff;

FIG. 3 shows a scanning electron micrograph of an aggregate of hairylactose particles after exposure to hot ethanol for 10 min;

FIG. 4 shows a scanning electron micrograph of lactose particles of FIG.1 after exposure to 50 ml ethanol vapour;

FIG. 5 shows a scanning electron micrograph of pre-treated lactoseparticles of FIG. 4 after treatment with boiling ethanol for 10 seconds;

FIG. 6 shows a scanning electron micrograph of spray-dried lactoseparticles after treating with boiling ethanol for 60 seconds;

FIG. 7 shows a scanning electron micrograph of spray-dried lactoseimmersed in ethanol at ambient temperature for 45 minutes. Note thatthese particles have micron-size hairs;

FIG. 8 a shows an original spray-dried lactose particle before treatingwith ethanol vapour;

FIG. 8 b shows spray-dried lactose particles after treating with 50 mlethanol vapour;

FIG. 8 c shows a golf-ball type surface textured lactose particle withnano-projections were obtained after treating with 120 ml ethanolvapour;

FIG. 9 shows a scanning electron micrograph after treating vapourtreated partially architectured lactose particles, shown in FIG. 8 c,with hot ethanol for 40 seconds;

FIG. 10 shows spray-dried lactose-PVA particles before treating withboiling ethanol;

FIG. 11 shows a scanning electron micrograph of lactose-PVA particlesafter treating in boiling ethanol for 30 seconds;

FIG. 11.1 shows a scanning electron micrograph of lactose-PVA particlesafter treating in hot ethanol for 60 seconds;

FIG. 12 shows a scanning electron micrograph of spray-dried lactose-PVPparticles;

FIG. 13 shows a scanning electron microscopy of spray-dried lactose-PVPparticles after treating with boiling ethanol for 60 seconds;

FIG. 14: Frozen Lactose particles obtained by freezing lactose dropletsin liquid nitrogen (the scale bar is that of a 15 cm ruler);

FIG. 14.1: Lactose particles obtained by freezing lactose dropletsfollowed by treating, for 5 mins, with ethanol/acetone mixturecontaining PVP as an excipient;

FIG. 15 shows a scanning electron micrograph of lactose particlesobtained by freezing lactose droplets followed by treating thesedroplets, for 5 minutes, with ethanal/acetone mixture containing PVP asan excipient;

FIG. 15.1 shows the detailed structure of a particle shown in FIG. 15;

FIG. 16 shows a scanning electron micrograph of lactose particles coatedwith fluticasone hairs;

FIG. 17 shows a scanning electron micrograph of lactose particles, whichhave been vapour-architectured twice with ethanol alone;

FIG. 18 shows a scanning electron micrograph of lactose particles whichhave been vapour-architectured twice with ethanol alone, followed by athird vapour architecture with ethanol/water mix;

FIG. 19 shows a general view of spray-dried lactose-PVP (24,000 MW)particles;

FIG. 20: Scanning electron micrograph of lactose—PVP particlearchitectured with ethanol vapour containing BDP (as an agent);

FIG. 21 shows a scanning electron micrograph of spray-dried lactoseparticles architectured by a fine mist formed from a 94/6% ratio ofethanol/water containing lactose;

FIG. 22.1 Particle size distribution of untreated Microfine lactoseusing a Sympatec Helos Particle Size analyser at 1 Bar dispersionpressure;

FIG. 22.2 Particle size distribution of treated Microfine lactose(treated with Liquid Nitrogen vapour) using a Sympatec Helos ParticleSize analyser at 1 Bar dispersion pressure;

FIG. 22.3 Particle size distribution of treated Microfine lactose(treated by immersion in Liquid Nitrogen) using a Sympatec HelosParticle Size analyser at 1 Bar dispersion pressure;

FIG. 2.4 Particle size distribution of treated Microfine lactose(treated by a combination of immersion in Liquid Nitrogen and treatmentwith Liquid Nitrogen vapour) using a Sympatec Helos Particle Sizeanalyser at 1 Bar dispersion pressure;

FIG. 22.5 Particle size distribution of untreated Microfine lactoseusing a Sympatec Helos Particle Size analyser at 3 Bar dispersionpressure;

FIG. 22.6 Particle size distribution of treated Microfine lactose(treated with Liquid Nitrogen vapour) using a Sympatec Helos ParticleSize analyser at 3 Bar dispersion pressure;

FIG. 22.7 Particle size distribution of treated Microfine lactose(treated by immersion in Liquid Nitrogen) using a Sympatec HelosParticle Size analyser at 3 Bar dispersion pressure;

FIG. 22.8 Particle size distribution of treated Microfine lactose(treated by a combination of immersion in Liquid Nitrogen and treatmentwith Liquid Nitrogen vapour) using a Sympatec Helos Particle Sizeanalyser at 3 Bar dispersion pressure;

FIG. 23.1:Standard twin stage impinger (TSI) of Apparatus A as describedin the British Pharmacopoeia, BP 2001;

FIG. 23.2: mTSI showing the attachment of the coupling tube to themicroscope stub;

FIG. 23.3 Scanning electron micrograph of engineered long time offlight, hairy lactose particles, having an aerodynamic diameter lessthan 6.4 micrometers, deposited on the lower stage of a modified twinstage impinger. Note that the geometric diameter of the particle is atleast 60 micrometers;

FIG. 23.4 Scanning electron micrograph of lactose hairs and fragmentedhairy lactose particles having an aerodynamic diameter less than 6.4micrometers;

FIG. 24 Comparison of cones formed by untreated microfine lactose andmicrofine lactose treated according to the fourth embodiment;

FIG. 25.1 Particle size distribution of untreated Spray-dried lactoseusing a Sympatec Helos Particle Size analyser at 1 Bar dispersionpressure; and

FIG. 25.2 Particle size distribution of Spray dried lactose vapourarchitectured using 260 ml of ethanol with a Sympatec Helos ParticleSize analyser at 1 Bar dispersion pressure.

DETAILED DESCRIPTION OF THE INVENTION

The present invention exists in more than one embodiment. The firstembodiment of the present invention is provided in the form of a methodof treating particles to enhance their ability to perform certainfunctions, but particularly the delivery of drugs to a target region ina patient. The method of the present invention enables particles to beengineered with the appropriate chemical, morphological and/or physicalfeatures for any particular task.

A second embodiment of the present invention exists in the form of theparticular particles engineered by the controlled treatments of theabove mentioned method. This second embodiment details typical particleand powder engineered features that are controllable using the methodsof this invention. It is appreciated that such particles can beengineered to deliver an active agent, e.g. a therapeutic agent, to atarget region of a patient. The types of engineered features isdependent on the type of agent being transported and the chosen pathwayof the delivery. Typical delivery routes are considered to be oral,parenteral, nasal, pulmonary, rectal, tonsillar, buccal, intraocular,topical/transdermal, vaginal. However, the preferred administrationroutes are oral, nasal, pulmonary and rectal.

A third embodiment of the present invention relates to a particularfamily of therapeutic agent delivery particles, i.e. carrier particlesfor the delivery of drug via inhalation in to the lungs. The carrierparticles of this embodiment have specific engineered features whichmake them better suited for the delivery of drugs deep into the lungs.The present invention provides carrier particles with improved lungdeposition of therapeutic agents. These improved carriers are low indensity and tend to have non-smooth (e.g. containing pores or hairsaccording to the invention) surfaces. As was discussed earlier in thisdocument, it is appreciated that both of these characteristics runcontrary to the accepted prior art.

A fourth embodiment of the present invention is the application of themethod of the invention for micronising, mixing and achitecturingparticle in one step. This embodiment relates to a process ofmicronising without using conventional milling, spray drying orconventional crystallisation techniques to produce ultra fine particles.These ultra-fine particles are attached to particles of the same size orof larger size to form a stable uniform mix avoiding segregation.Another aspect of fourth embodiment is the introduction of the particlesinto bulk fluid

A fifth embodiment of the present invention is the application of themethod of the invention in an innovative MELT BACK crystallisationprocess to produce particles with the required physico-chemical andmorphological features.

In order for the present invention to be understood the followingguidelines for carrying out the method of the invention are given below,followed by examples of more specific methods of treating particles toengineer desirable chemical, morphological and/or physical features.

The method of the present invention provides a means of engineeringparticles to give them particular morphological, chemical and/orphysical features and these such features imparted to particle improvetheir formulation and delivery capabilities.

Important formulation capabilities include surface restructuring toreduce cohesion and hence improve flow properties, improved particlecrystallinity (hence improved stability), modify particle mechanicalproperties. Transfer of at least one agent (to the particles toestablish a stable uniform mix), ease of particle mixing, formation ofstable uniform mix, prevention of particles segregation. Importantdelivery capabilities include particle aerodynamic properties, powdersurface area, hollow volume, dissolution rate, solubility, controlledrelease of therapeutic agent, maintenance of the particle at the site ofaction, targeting different and specific regions of the airways.

The method of treating particles to engineer them with particularchemical, morphological and/or physical features, comprising the stepsof:

-   a) processing at least one agent to form a particle;-   b) treating by making available a fluid alone or in combination with    at least one additive to the particle (processed or unprocessed) to    promote changes in the chemical, morphological and/or physical    features of the particle;-   c) repeating step (b) as many times as necessary;-   d) harvesting engineered particles; and repeating steps (a) to (d)    as many times as necessary.

Preferably the particles to be treated is as obtained from the supplieror manufacturer without any further modifications.

Preferably the method of producing particles suitable for engineering bypresent method should produce particles of a narrow particle sizedistribution, particles of controllable size and these particles arepreferably smaller than the particle size required for the intendedpurpose.

Suitable particles for engineering by the method of the presentinvention can be produced by various methods include but not limited to:spray drying, micronisation, granulation, sieving, fractioning,freezing, freeze drying, spray freezing, spray freeze drying,spray-chilling, spray congealing, spray cooling, freeze fracturing,spray freeze fracturing, emulsion solvent evaporation/extraction,coacervation, extrusion spheronisation, coating of nonpareil spheres,pelletization, wet granulation, dry granulation, crystallization or‘MELT BACK crystallisation’.

One of the preferred methods of producing particles suitable forengineering by the present method is that of spray drying as it resultsin particles of controllable size with a narrow size distribution. Sucha process is known to suitably produce particles from various materials(e.g. lactose).

Another preferred method of producing particles suitable for engineeringby the present method is that of spray freezing, spray congealing asthey produce particles of defined size and shape.

Another preferred method of producing particles suitable for engineeringby the present method is that of MELT BACK crystallisation.

Preferably the particles to be treated are spherical in shape, and mostpreferably the particles are hollow and spherical in shape especiallyfor inhalation purposes.

The particles to be treated can be in any state of matter. Suitablestates of matter of the particle include but not limited to: solid,liquid, gas (ideal, real or mixtures thereof), vapour, supercriticalfluids, solutions, suspensions, dispersions, emulsions ormicro-emulsion, colloids, liquid crystals, visco-elastic, gels, waxymaterial, slurry, paste, semi-solid, molten, frozen states andcombinations thereof.

Preferably the particles to be treated are in the solid state, liquidstate (as droplets or droplets of the molten state), vapour or thefrozen state.

In the method of the present invention the particles are treated with afluid to promote the engineering of desirable chemical, morphologicaland/or physical features in the particles as well as transfer of atleast one agent to the particle. It will be appreciated that the fluidcan be made up of one or more mediums. The medium(s) of the fluid can bein different states of matter. In situations where the fluid comprisesmore than one medium it is preferred that the mediums of the fluid aremiscible. The fluid can also comprise one or more constituents. Bothconstituents and mediums are agents which can or cannot be combined withan additive. The fluid may also contain agents as constituents, whichare or are not present in the particle. Equally, the particle cancontain agents that are or are not present as constituents of the fluid

Suitable states of matter of the fluid include but not limited to:solid, liquid, gas (ideal, real or mixtures thereof), vapour,supercritical fluids, solutions, suspensions, dispersions, emulsions ormicro-emulsion, colloids, liquid crystals, visco-elastic, gels, slurry,paste, semi-solid, molten, frozen states and combinations thereof.

Preferably, the fluid is in the liquid state or vapour state. It isunderstood that these two states of matter may be comprised ofsolutions, suspensions, emulsions and colloids

Preferably the fluid used in the method of the present invention is inthe liquid state. More specific examples of suitable mediums to make upthe fluid include: water; hydrocarbons solvents; mineral spirit; mineraloils; halogenated solvents, such as methylene chloride and bromide,freons, bromo-chloro-methane, chloroform and carbontetrachloride;oxygenated solvents, such as ketones, ethers, esters, carboxylic acids,aldehydes, alcohols and carbonates; nitrogen containing solvents, suchas amines and amides; sulphur containing hydrocarbon solvents, such assulphoxides and sulfonates; and other hetero-atoms containinghydrocarbon solvents; mineral acids, such as sulfonic acids, sulphuricacids, phosphoric acids, nitric acids and anaesthetics such ashalothane, enflurane, isoflurane, methoxyflurane, sevoflurane. Yet morespecific examples are liquefied gases e.g. liquid nitrogen (boilingpoint −196° C.), liquid oxygen (boiling point −183° C.), liquid argon(boiling point −186° C.), chlorofluorocarbons, fluorocarbonatedrefrigerants (such as dichlorodifluoromethane, perfluoropropane, CF4,C2F6, C3F8, C4F8, C2F4, C3F6), hydrofluoroalkanes (such as HFA-134a,HFA-227) or any liquid medium(s) (described hereinabove) that cangenerate a vapour. The fluid can be used in the temperature range of−200 to 200° C.

Preferably a suitable ketone is acetone, a suitable alcohol is ethanoland a suitable liquefied gas is liquid nitrogen.

The agents comprising the particle can be completely soluble, completelyinsoluble or have partial solubility (anywhere in between soluble andnon-soluble) in the fluid.

Preferably at least one agent of the particle should have limitedsolubility in the fluid.

The step of treating the particles with the fluid can, in onealternative of the present invention, involve introducing the fluid tothe particle, in this instance the particle may be static or in motion.The fluid can be introduced at any rate, in any state of matter, and inbulk, as droplets, as a mist, as a fog, as a spray or combinationsthereof. Alternatively, the particles are introduced to the fluid, inthis instance also the fluid may be static or in motion, with suchintroduction being at any rate in any state of matter, and in bulk, asdroplets as a mist, as a fog, as a spray or combinations thereof.

Preferably the step of treating the particles with the fluid lasts forbetween 1 microsecond and several hours. However, more preferably, thetreating step lasts for between 1 microsecond and 60 minutes.

The step of treating the particles with the fluid can occur at the pointof particle manufacture, wherein for example, the particles are fully orpartly formed and then treated with the fluid, alternatively theparticles can be engineered in the fluid as the particle crystallizes orforms within the fluid as in melt-back crystallisation.

Before, during or after treating particles with the fluid, additives canbe applied to the particle, fluid or both in order to engineer therequired features of a particle for the particular task.

Additives generally include but not limited to such factors as: heat(directly or resulting from the application of laser energy ormicrowaves), moisture, radiation (laser light, microwaves), pressure,vacuum, shear forces, magnetic forces, vibration, systems of agitation,stirring, rotation, tumbling, vortexing, centrifuging, masticating,ultra-sound waves or extruding and electrical, although any factor orcombination of factors that favour changes in the chemical,morphological and/or physical features of a particle are desirable. Forexample the use of stirring and heat increases the speed and extent ofparticle growth, hair growth and pore size and uniformity in the changeof the particle properties.

It is also further appreciated that before, during or after treating theparticles with the fluid at least one further agent can be applied (oradded) to the particle, fluid or both in order to engineer the requiredfeatures of a particle for the particular task. For example agentsincorporated (or added) to the particle and agents added to the fluidaid the formation and growth of hairs, impart plastic behaviour to theparticle, maintain the spherical shape of the particle and transferagents from the fluid onto the particle.

Preferably the agent(s) can be either a therapeutic agent, prophylacticagent, diagnostic agent or an excipient. It is also appreciated thatmore than one of such agents may be used in combination to create theengineered particles of the present invention. Other materials commonlyused in pharmaceutical compositions, such as diluents, flavourants,fragrances, dyes, nutrients and sweeteners are also considered aspossible agents within the understanding of the present invention.

Suitable nutrients include: retinoids such as all-cis retinoic acid,13-trans retinoic acid and other vitamin A and beta carotenederivatives, vitamins D,E,K and water insoluble precursors andderivatives thereof.

The therapeutic agents, prophylactic agents and diagnostic agents of thepresent invention are preferably taken from the group comprising:peptides, proteins, organic substances, inorganic substances, pro-drugs,antigens and hormones.

More specific examples of agents that can be treated under the presentinvention include: corticosteroids; anti-inflammatories such asbeclomethasone, betamethasone, fluticasone, flunisolide, budesonide,dexamethasone, tipredane, triamcinolone acetonide; anti-tussives such asnoscarpine; and bronchodilators such as ephedrine, adrenaline,fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine,phenyl propanolamine, pirbuterol, reproterol, rimiterol, salbutamol,salmeterol, formoterol, terbutaline, isoetharine, tulobuterol,orciprenaline and (−)-4-amino-3,5-dichloro-α[[[6-[2-(2pyridinyl)ethoxy}hexyl]amino]methyl]benzenemethanol,

Further specific examples of suitable agents include: the diureticamiloride; anticholinergics such as ipratropium, ipatropium bromide,atropine, oxitropium and oxitropium bromide; hormones such as cortisone,hydrocortisone and prednisolone; and xanthines such as aminophylline,choline theophyllinate, lysine theophyllinate and theophylline.

Yet further specific examples of suitable agents include: analgesicssuch as codeine, dihydromorphine, ergotamine, fentanyl and morphine;diltiazem which is an anginal preparation; antiallergics such ascromoglycate, ketotifen and nedocromyi; anti-infectives such ascephalosporin, penicillins, streptomycin, sulphonamides, tetracyclinesand pentamidines; and the anti-histamine methapyrilene.

Yet further specific examples still include: anti-neoplastic agents likebleomycin, carboplatin, methotrexate and adriamycin; amphotericin B;anti-tuberculous agents such as isoniazide and ethanbutol. Therapeuticproteins and peptides (e.g. insulin and glucagon, prostaglandins andleukotrienes) and their activators and inhibitors including prostacyclin(epoprostanol), and prostaglandins E, and E2 are also considered to makesuitable substances for treatment using the method of the presentinvention.

It will be appreciated to the artisan that, where appropriate, the abovelisted therapeutic agents may be used in the form of salts (e.g. asalkali metal or amine salts or as acid addition salts) or as esters(e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise theactivity and/or stability of the therapeutic agent.

Preferably, where the agent is a therapeutic agent it will either be ananti-inflammatory drug or a bronchodilator. More specifically thepreferred therapeutic agents of the present invention are beclomethasonedipropionate, salbutamol sulphate and fluticasone propionate.

Preferably, when the excipient is used on its own to produce particlesand not in combination with any other type of substance (i.e.therapeutic agents, prophylactic agents and diagnostic agents) suchexcipients are sugars, preferably taken from the group comprising:monosaccharide, disaccharide, polysaccharide and sugar alcohols such assorbitol, mannitol, maltitol. Further preferably the excipient islactose.

It is also appreciated that more than one of the above agents may beused in combination to produce the particles of the present invention.Suitable combinations comprise a short acting β₂ agonist and anantimuscarinic, typically salbutamol and ipatropium bromide; orfenoterol and ipatropium bromide. Alternatively the combination of ashort acting β₂ agonist and a corticosteroid in the form of salbutamoland beclomethasone is advantageous. A further alternative is thecombination of a long acting β₂ agonist and a corticosteroid, typicallysalmeterol and fluticasone; or eformoterol and budesonide.

As discussed above, the combination of one or more therapeutic agent,prophylactic or diagnostic agent (as listed above) with one or morepharmaceutical excipients is also considered desirable within thepresent invention. The excipients suitable to be used in combinationwith therapeutic agent are not necessarily the same as those that areappropriate when a particle is produced from an excipient alone.

The presence of an excipient in combination with a therapeutic agent canfacilitate a retarded, controlled, sustained or targeted release of thetherapeutic, prophylactic or diagnostic agent. According to the presentinvention excipients can act to regulate the release, such excipientsare preferably either non biodegradable, biodegradable or bioerodiblepolymers.

More specifically, suitable polymers include but not limited to:cyclodextrins and derivatives thereof, sodium caseinate, dipalmitoylphosphatidyl choline (DPPC), human serum albumin, phospholipids,cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, carboxymethylcellulose, methyl cellulose, cellulose acetate butyrate, poloxamer,poly(lactic acid), poly(lactic-co-glycolic acid), poly(lactide)s,poly(glycolide)s, poly(lactide-coglycolide)s, poly(p-dioxanones),poly(caprolactone), polycarbonates, polyamides, polyanhydrides,poly(alkylene alkylate)s, polyamino acids, polyhydroxyalkanoates,polypropylenefumarates, polyorthoesters, polyacetals, polyacrylamides,polycyanoacrylates, polyalkylcyanoacrylates, polymetha polyphosphateesters, polyphosphazene, polyurethanes, polyacrylates, polymethacrylate,poly(methyl methacrylate), poly(hydroxy ethyl methacrylate-co methylmethacrylate), carbopol 934, ethylene-vinyl acetate and other acylsubstituted cellulose acetates and derivatives thereof, polystyrenes,polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl chloride, polyvinylfluoride, poly(vinylimidazole), chlorosulphonated polyolefins,polyethylene, polyethylene glycols, polypropylene, polyethylene oxide,copolymers and blends thereof.

Preferably, the selected polymer is biocompatible in that it degrades orerode in-vivo to form non-toxic small molecules. More preferably, thebiocompatible polymer is pharmaceutically acceptable for delivery to therespiratory tract. Even more preferably, the polymer is bothpharmaceutically acceptable to the lung and has therapeutic properties.

In another preferred aspect, the selected polymer imparts to theresulting particles a plastic nature. Examples of polymers that impart aplastic nature to the particles are Polyvinyl alcohol,Polyvinylpyrrolidorie and polyethylene glycol (PEG).

In another preferred aspect, agents other than the polymer can impart tothe particle a plastic nature.

In another preferred aspect, the fluid (with or without additives) canimpart to the particle a plastic nature directly or by the transfer ofagents with a plastic nature to the particles.

In another preferred aspect, the selected agent may impart to theparticle a brittle nature.

In another preferred aspect, the fluid (with or without additives) canimpart to the particle a brittle nature.

In view of the above comments, preferable excipients for use incombination with one or more therapeutic, prophylactic or diagnosticagent are cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, polymeric drugs and genetically engineered polymers.

The agent or agents to be treated might contain one or more stabilisersto protect the therapeutic agent from degradation and maintain thebiological activity. The term stabilisers as described herein means anyagent which binds or interacts in a covalent or a non-covalent mannerwith the therapeutic, prophylactic, diagnostic agent or excipient.Suitable stabilisers that can be used in the present invention will beappreciated by the skilled man (see for instance U.S. Pat. Nos.5,716,644; 5,674534; 5,654,010, 5,711,968; 6,284,283). However,preferred stabilising agents include: sucrose, trehalose, polyvinylpyrrolidone and dextran.

It is appreciated that the agent in the particles and/or in the fluidcan have preservative, antiseptic, disinfection and/or sterilisationproperties. When these agents are combined with additive such as heat orradiation increases the efficiency of preservation, antiseptic,disinfection and/or sterilisation effects.

Suitable preservative, antiseptics, disinfectants and sterilising agentsinclude but are not limited to: phenolics (such as: phenol, cresols,xylenols), halogenated phenolics (such as, chlorocresol, chloroxylenol,hexachlorophene, triclosan), alcohols (such as, ethanol, benzyl alcohol,bronopol, phenoxy-ethanol), aldehydes (such as, formaldehyde,glutaraldehyde), organic acids and their ester, quaternary ammoniumcompounds (such as, cetrimide, benzalkonium chloride), biguanides (suchas chlorhexidine, polyhexamethylene biguanide), amidines (such as,propamidine, dibromopropamidine), halogens and their compounds (such as,hypochlorous acid, Eusol, Chloronated Soda solution, chloramines T,halozone, potassium iodide, iodophores, betadine), Metal ions (such as,mercury, silver, aluminium, phenylmercuric nitrate and acetate,thiomersal), acridines (such as, aminacrine hydrochloride), gases (suchas ethylene oxide, formaldehyde, β-propiolactone, propylene oxide,methyl bromide, gas plasmas in combination with heat or radiation).

Wherein the fluid itself either in liquid or vapour state haspreservative, antiseptic, disinfectants, sterilising properties inaddition to architecturing the particles. The liquid sterilising agentis an alcohol in this case ethanol and the vapour state is steam.

In a further aspect of this embodiment the material of the particle issoftened by treating with the fluid, the frequency and energy of theradiation source (laser light or microwaves) may be matched with thephysico-chemical properties of the particle such that the radiationcauses fracturing, dimpling of the particle or if the particle is hollowforming holes within the particle or ablating the particles.

It will be appreciated that the above discussed additives can beutilised at any stage or stages a) to d) of above described method.

It will be appreciated that the treatment of a particle with aparticular selection of agents and environmental additives will resultin the formation of a particle with a particular set of chemical,morphological and/or physical features. Some of the features may bedesirable for the chosen task of the engineered particle, whereas somefeatures may not. In such circumstances it is appreciated that apre-treated particle, produced by the treatment with a first set offluids, mediums, agents and additives, can be subjected to furthertreatment with another particular selection of fluids, mediums, agentsand additives (such treatments can be repetitions of the earliertreatment or alternative treatments).

Important morphological features that can be engineered on particlessubjected to the present invention include: hairs; spongy-likeformations; porous; surface dimpling, particle shape, particle surfacetexture, transfer of at least one agent to the particle and combinationsthereof. More specifically for pores, the size, shape and number of thepores is important. The term hair, used throughout this specification isconsidered to include any type of projection present on the surface of aparticle. Such projections can be of any shape (e.g., needle, plates,blade, fluffy), size, texture, density and have any mechanical property,(e.g., elastic, brittle, plastic, glassy). Preferably any engineeredhairs are within the range of 0.001 micrometers to 5000 micrometers inlength.

Important chemical and physical features that can be engineered to theparticle subjected to the present invention include: particle size,density, specific surface area and surface texture; mechanicalproperties such as friability, tensile strength, elastic, brittle,plastic, glassy and rubbery states; polymorphism or crystallinity;solubility and dissolution rate; aerodynamic properties, hygroscopicity,cohesiveness, particle hollow volume, ability of the particles of thepresent invention to improves blend homogeneity, improves theaerosolization and deposition of highly cohesive and poor flowingparticles, the result of transfer of at least one agent.

A suitable size for particles is considered to be between 0.05 and 4000μm in diameter, furthermore for particles intended for inhalation or ascarrier for inhalation are of a preferred particle size between 0.05 and200 micrometers. The most preferred particle size for inhalation or ascarrier for inhalation is between 0.5 and 60 micrometers.

It will become apparent to the artisan, herein below, that one or morefeatures of the particle can be engineered whilst maintaining the otherfeatures

The particle size can be determined by conventional particle sizemeasuring techniques known to those skilled in the art, such as, laserdiffraction, photon-correlation spectroscopy, sedimentation, field-flowfractionation, disc centrifugation or electrical sensing zone; the mostpreferable being laser diffraction.

In one aspect of the second embodiment, the process of the presentinvention reduces the particle size by over 1000% whilst maintaining theoriginal shape and the particles are mono-disperse. In FIG. 14 thestarting particle is as small as 3 mm in diameter whilst the finalparticles have a maximum diameter of 30 micrometers (FIG. 14.1). Thisrepresents a phenomenal reduction in particle size whist the originalshape of the particles is maintained, in addition, hairs areadvantageously produced.

The process of the present invention can maintain the particle size(Examples 2, 4,9 and 11), compare FIGS. 4, 8 b, 8 c, 20, 21 with that ofthe starting particles of FIGS. 1, 8 a and 19.

Preferably the process of the present invention enables controlledgrowth in the particle size. Compare the starting particle size of FIGS.1, 10 and 12 with the corresponding treated particles of FIGS. 2, 5, 6,7, 11,11.1,13,16 (Examples 1, 2, 3, 5, 6 and 8). From FIG. 7 it is clearthat the particle grows to at least 70 micrometers.

To exemplify that the present invention can control the size of theresultant particles the following table list examples of Figuresachieving a certain particle size. Particle Size Figures in which theparticles (micrometers) are of this range 10 or below 4, 8a, 8b, 11.1and 18 20 6 and 16 30 5, 11, 14.1 60 13 70 2 and 7 80 9

Thus with this invention it is possible to control the particle size andproduce particles much greater than 80 micrometers by manipulating atleast the treatment time, treatment temperature and treatmentconditions.

It should be apparent to the skilled artisan that the growth and size ofthe resultant particles is dependent upon the size of the startingparticle. Hence if a large particle is required the preferred startingparticle size should also be large.

In the current invention the particle size can be manipulated over asize range of 5 mm, the preferred particle size control range is 200micrometers and the most preferably particle size control range is 80micrometers

In another aspect of the second embodiment, the process of the presentinvention preferably enables the alteration of the particle density (seeexample 2, FIGS. 5,6,11.1,15,18 and 20 by altering treatment conditionsor mass transfer FIG. 16).

The powder was carefully poured into a 50 ml volumetric cylinder and theparticles bulk density was calculated by dividing the weight of powder(gm) by the volume occupied by the powder bed (ml). The results areshown below. Bulk density Example in Material (gm/ml) figure no. Spraydried lactose 0.276 1 Liquid vapour introduced to 0.240   8c the lactoseparticles Lactose particles added to the 0.182 6 liquid fluid

It is clear that by changing the method in which the particle isengineered it is possible to manipulate the density

In yet another aspect of the second embodiment, the process of thepresent invention preferably reduces the cohesiveness, adhesiveness andenables improvement in the powder flow (Examples 14 and 16). Treatmentwith the vapour of low temperature liquid gases and or immersion in lowtemperature liquid gases were extremely effective in reducing cohesionbetween particles (Example 13). To those skilled in the art, it shouldbe apparent that particles with minimal adhesion and cohesion areexcellent for dry powder inhalers.

In a further aspect of the second embodiment, the process of the presentinvention preferably maintains the particle shape (see all the examplesand all the figures).

In the background of the invention, the importance of spherical shapedparticles was described in the examples presented, the startingparticles and final particles were spherical, thus the method of theinvention maintains the preferred spherical shape.

In a still further aspect of the second embodiment, the process of thepresent invention preferably form and/or modify hairs on the particles.The process of the present invention preferably controls the size of thehairs to produce nano-sized projections (FIGS. 4,5,6, 8 c), micron sizedprojections (FIGS. 2,7,11,11.1,15) and projections that are larger thanthe particle core (FIG. 7).

Further, the process of the present invention also preferably controlshair shape to obtain, for example, crystalline hairs (FIGS. 2 and 7),fluffy hairs (FIG. 11.1), blade-like hairs (FIG. 15), hairs tangentialto the surface of the particle (FIG. 16) and plate-like hairs.

Furthermore, the process of the present invention also preferablycontrols the nature of hairs, for example, in producing crystalline,elastic and brittle hairs which can detach from the particle (FIGS. 2and 7) or hairs that exhibit a plastic nature resulting from theincorporation of a plastically deforming material such as PVP (FIG. 13)or PVA (FIG. 11.1) into the particle or the use of an additive such asheat to induce a material that is normally brittle to produceplastically deforming hairs (FIG. 6).

The hairs formed on the particle can be combinations of hairs produceddirectly from the agent(s) of the particle (FIG. 2) or may be the resultof the transfer of at least one agent to the particle from the fluid(FIGS. 16 and 20).

In another aspect of the second embodiment, the process of the presentinvention preferably changes the mechanical properties of the particlesand hairs.

The process of the present invention can preferably induce a brittlenature to the particles and the hairs (FIGS. 2 and 7). Treating theparticles with low temperature liquid gases (such as liquid Nitrogen asin Example 13) are known to induce a brittle nature to the particletreated.

Furthermore, the process of the present invention can preferably inducea tendency of the particles to deform plastically (FIGS. 11, 11.1 and13). This change in particle mechanical properties results from thenature of the agents of the particle, nature of agents introduced to theparticle and/or treatment conditions such as the use of heat.

The advantages of using liquid nitrogen or liquid nitrogen vapour andtheir combinations is that it is applicable to both water soluble andwater insoluble agents. With liquid nitrogen, considerably greaterevaporation rates, at considerably lower temperatures, is obtainable.Consequently the low temperature is less likely to affect heat sensitivematerials and is therefore applicable to proteins, peptides,macro-molecules and heat sensitive agents. The high evaporation rategives a high specific area of contact between liquid nitrogen vapour andthe particles thereby reducing the treatment and drying time. Vapoursare also known to reduce the electrostatic charges between the particlesreducing cohesiveness, adhesion and improving flow properties of thepowder as detailed in the second embodiment. Liquid nitrogen is alsoenvironmentally friendly. Heat may impart to the particle a plasticnature.

In another aspect of the second embodiment, the process of the presentinvention, further and preferably modifies the surface texture forexample from smooth surfaces to increasing degrees of surface roughness,All figures except FIGS. 1, 2.1, 8 a, 10, 12 and 19, Examples 1 to 12).

In another aspect of the second embodiment, the process of the presentinvention preferably form or modify pores in number, shape and size(FIGS. 4,6, 8 c [golf ball-like], 11.1, 17, 18, 20 and 21 see Examples0.2, 3, 4, 5, 9, 10, 11 and 12).

In another aspect of the second embodiment, the process of the presentinvention preferably maintains or increases particle hollow volume(FIGS. 2, 5, 6, 11, 11.1 and 13, see Examples 1, 2,3, 5 and 6).

In another aspect of the second embodiment, the process of the presentinvention preferably gives the operator control of the specific surfacearea of the particle (see example 7).

It is known that the specific surface area of a spherical particle isthe ratio of the surface area of the sphere (4πr²) divided by the volumeof said sphere (4πr³/3)${{Specific}\text{-}{surface}\text{-}{area}} = {\frac{{Surface}\text{-}{area}}{Volume} = {\frac{4\quad\pi\quad r^{2}}{\frac{4}{3}\pi\quad r^{3}} = \frac{3}{r}}}$

From the above it is clear that the specific surface area increases asthe radius of the particle decreases. Hence control of the particle sizegives the skilled artisan control of the specific surface area and sincethe particle size can be controlled by the present invention then alsothe specific surface area can also be controlled as shown below.

The following tables list the radius, corresponding volume, surface areaand specific surface area of spherical particles produced according tothis invention. It is evident that the starting and final particles arespherical and that the starting particles have a minimum diameter of 3mm (see FIG. 14, with radius of 1.5 mm) whilst the final particles havean diameter of 30 micrometers (see FIG. 14.1. hence the radius is 15micrometers which is 0.015 mm). Surface area Specific Surface Radius(mm)Volume (mm³) (mm²) area (1/mm) Starting 1.5 14.14 28.27 1.999 particleFinal 0.015 0.0000141 0.00282 200 particle

It is clear that the process of this invention enables an increase inthe specific surface area of the particles.

Apart from increasing the specific surface area of the particle byreducing the particle size, the hairs and pores formed on the particlefurther increases the surface area of the particle thereby furtherincreasing the specific surface area of the particle.

Equally consider example 0.3. where the starting particle size of spraydried lactose is 2 micrometers (FIG. 1 this equates to a radius of 1micrometer which is 0.001 mm), after treatment with the process of thecurrent invention the final particle size is at least 20 micrometers(FIG. 6, equating to a radius of at least 10 micrometer which is 0.01mm). It is also clear that both starting and final particles arespherical in shape, hence the above equation is applicable. Putting thisdata in a similar table as above. Surface area Specific Surface Radius(mm) Volume (mm³) (mm²) area (1/mm) Starting 0.001 4.2 × 10⁻⁹ 1.3 × 10⁻⁵3100 particle Final 0.01 4.2 × 10⁻⁶ 1.3 × 10⁻³ 310 particle

It is clear that the process of this invention enables a decrease in thespecific surface area of the particles.

Hence the process of the present invention enables the skilled artisanto manipulate the specific surface area as required.

In another aspect of the second embodiment, the process of the presentinvention preferably forms or modify dimple on the particle (FIGS. 4, 8c see Examples 2 and 4).

In another aspect of the second embodiment, the process of the presentinvention preferably causes spongy-like formations (FIGS. 5, 6, 11, 11.1and 20 see Examples 2, 3, 5 and 11).

In another aspect of the second embodiment, the process of the presentinvention preferably modifies the aerodynamic properties of the particle(see example 15). From FIG. 23.3 it is clear that hairy particles of thepresent invention, with geometric mean diameters as large as 50micrometer deposit in the lower stage of the twin stage impinger andconsequently such particles should deposit in deep lung. This in itselfis contrary to the prior art, where particles with geometric meandiameter of 5 micrometers or less deposit in deep lung.

In another aspect of the second embodiment, the process of the presentinvention preferably transfers an ultra-fine agent to another particleof the same or larger size to form a stable mix (FIGS. 16 and 20 seeexamples 8 and 11).

In another aspect of the second embodiment, more preferably, the processof the present invention enables the control of combinations of theabove, i.e. particle size, hairs, surface area, hollow volume, particledensity, powder flow and transfer of an agent (FIG. 20 and example 11).

In another aspect of the second embodiment, the particles of the presentinvention preferably improves blend homogeneity composed of engineeredparticles of this invention and low dose drug (see example 16).

In another aspect of the second embodiment, the particles of the presentinvention preferably improves the aerosolization and deposition ofhighly cohesive and poor flowing particles, an example given for clarityis spray dried lactose (i.e. engineered particles mixed with spray driedlactose and aerosolised into a twin stage impinger see example 15).

A third embodiment of the present invention relates to a particularfamily of therapeutic agent delivery particles (i.e. carrier particles)for the delivery of drug via inhalation into the lungs, which can beproduced by the method of this invention. The carrier particles of thisembodiment have specific engineered features which make them bettersuited for the delivery of drugs deep into the lungs. The presentinvention provides carrier particles with improved lung deposition oftherapeutic agents. These improved carriers are low in density and tendto have non-smooth (e.g. containing pores or hairs according to theinvention) surfaces. As was discussed earlier in this document, it isappreciated that both of these characteristics run contrary to theaccepted prior art.

The carrier particles of the present invention is preferred to havehairs, more preferably the carrier particle should be hairy and porousor hairy and low density and most preferred the carrier particle ishairy, porous and of low density. It is further preferred that thecarrier particle has good aerodynamic properties and this may be theresult of manipulating combinations of the particles hairy, porous andlow density nature.

From the second embodiment it should be apparent to the skilled artisanthat this present invention enables the production and manipulation ofparticle hairs, pores, hollow volume and density. In addition, thepresent invention also reduces cohesiveness of the particles, improvesthe flow of the particles, improves aerosolization of the particles (byreducing both cohesive and adhesive forces) and good particle depositionto the lower stage of the twin stage impinger (See example 15). All theimprovements detailed above, consequently improve the aerodynamicproperties of the particles. The literature suggest that the effectivecut-off diameter for a twin stage impinger at 60 litres per minute is6.3 to 6.4 micrometers (Hallworth. G. W. & Westmoreland, D. G., 1987,The twin impinger: a simple device for assessing the delivery of drugsfrom metered dose pressurized aerosol inhalers, J. Pharm., Pharmacol.39, 966-972 and Miller et al, 1992, Assessment of the twin impinger forsize measurement of metered dose inhaler spray. Pharm. Res., 9,1123-1127). However, from example 15 and FIG. 23.3 the engineeredparticles of this invention, despite it's larger size (i.e. 40-50micrometer, FIG. 23.3) it still deposits in the lower stage of the twinstage impinger suggesting that it's aerodynamic diameter is less than6.4 micrometer and must be a consequence of the hairs, pores, hollowvolume and low density of the particle. Conventional carriers particlesremain in the inhaler device and or deposit in the mouth or on back ofthe throat hence they have a short time of flight. Whereas theengineered carriers of this invention must have travelled a longdistance to reach the lower stage of the twin stage impinger suggestingthat they have a much longer time of flight than conventional carrierparticles. The long flight time of the engineered carrier particles meanthat these particles can carry cohesive drugs into deep lung. Hence theadhesion and cohesion problems that are normally associated and areburdens for traditional carrier particles are of no consequence with thecarrier of the current invention. These particles are consequentlydesirable for deep lung penetration.

The present invention enables the production and manipulation of hairs.The presence of hairs on the particles gives the particle manyattributes some of which are detailed below. The hairs maintain thestability and content uniformity of the mix (example 17). The hairs arepart of the particles and can act as a ternary component that minimisescontact between the carrier core and therapeutic agent particle. Inaddition the hairs have a dynamic element whereby oscillation of thehairs improves detachment of adhered mono-disperse or poly-dispersetherapeutic agent particles from the carrier particles. A slightoscillation may be sufficient to detach the hairs from the particleduring the time of flight (See FIG. 2 which depicts some detached hairsbefore aerosolization). Some of the remaining hairs attached to theparticle and the particle itself, at impact, fragment ejectingconsiderable quantities of hairs and particle fragments over an areasubstantially larger than the impact site (See FIGS. 23.3, 23.4 andexample 15) giving a “cluster-bomb” like effect. This consequentincrease in lung contact area is pharmacologically important in that alarger area of the lung is treated at any one time compared toconventional particle thus making these particles more economic as alarger area of the lung is treated with minimal amount of the drug. As aresult pharmacological bioequivalence is achieved using a smaller amountof engineered drug particles compared to the larger amount of drug usedin the conventional inhaler systems. Giving considerable cost savingsespecially in cases where the drug is expensive whilst minimisingunwanted side effects. The increased surface area conferred to theparticle by the hairs automatically improves the aerodynamic propertiesof the particle as well allowing more therapeutic agent particles to beadhered to one carrier particle, thereby reducing the carrier particle:therapeutic agent particle ratio. Further, the hairs can be produced ofbioadhesive agents which at the point of carrier impaction allow thehairs to act as grappling hooks achoring the carrier particle to theimpact site. Furthermore, the mechanical properties(elastic/brittle/plactic behaviour) of the hairs can be manipulated toprevent bouncing of the particles in the lung epithelia, this bouncingeffect is a source of expiration of small particles from the lungs.

The present invention, preferably maintains the spherical shape of thecarrier particle and as detailed, above in the background to theinvention and summary of the invention, spherical particles gives theparticles many attributes some of which are detailed below. Sphericalparticles are easier to mix than any other shape. Spherical particleshave optimal flow properties due to minimal inter-particulate contactand minimizes segregation. The improved flow properties resulting fromthe spherical shape of the particles enable easier and totalaerosolization of the powder.

The present invention, further, preferably enables control of theparticle size (whether by shifting over-size particles to undersizeparticles or controlled growth of the particles to the required particlesize), density (by transferring agents to the particle to increase thedensity or manipulating the treatment conditions to decrease density orcombinations thereof), the pores of the particle and the hollow volumeof the particle all of which alters the aerodynamic properties of theresultant particle. The carrier particles of the third embodiment arepreferred to be of low density and preferable aerodynamic diameter. Thelatter is achieved by controlling and or manipulating the particle size,particle hollow volume and particle pores according to the equationd_(a)=d_(g)(ρ_(p)/ρ₀χ)^(0.5), the skilled artisan should appreciate thatmodification of these parameters also modifies the particle density. Thelow density carrier with favourable aerodynamic diameter permits easyand total aerosolization of the formulation, reduces cohesiveness of theparticles, facilitates a long flight time of the carrier that in turnallows more time for the therapeutic agent particles to detach. Theoscillation of hairs on such low density, aerodynamically favourableparticles promote further detachment of therapeutic agent particles fromthe carrier. Those therapeutic agents particles which do not detach fromthe carrier particles are carried to deep lung to the impact site of thelight, low density carrier particle where the bioadhesive and anchoringfunctions of the hairs retain the therapeutic agent at the lungepithelia for sufficient a time to enable therapeutic agent transfer tothe lungs. The carrier particle of the third embodiment consequentlydelivers more therapeutic agent to the site of action in deep lung.

Hence, for the carrier of the third embodiment, the adhesion problemsassociated with conventional inhaler devices are of no consequence asthe carrier of the third embodiment travels to deep lung. Hence thetherapeutic agents may coat the hairs of the particle, coat the particle(as described in the fourth embodiment or otherwise), be strongly orweakly adhered to the carrier particle. Further the carrier particles ofthe third embodiment can thus be used to carry conventionally prepared(i.e. milling, spray drying and crystallisation) therapeutic agentsparticles or therapeutic agent particles prepared according to theembodiments of this invention. Furthermore, the amount of carriertravelling to deep lung is reduced as increased surface area imparted tothe carrier particle by the hairs increases the drug loading perindividual carrier particle.

Advantageously, the engineered carrier may be composed of 100%therapeutic agent, thus allowing the therapeutic agent to be deliveredon its own or act as a carrier for one or more therapeutic agentparticles The carried therapeutic agent particles can be traditionallyprepared or engineered according to the current invention.

The fourth embodiment of the present invention is the application of themethod of this invention to a process of micronising and mixing in onestep that by passes the limitations of the current state of the art inmicronising and mixing. This embodiment relates to a process ofmicronising without using conventional milling, spray drying orconventional crystallisation techniques to produce ultra fine particles.These ultra-fine particles are attached to particles of the same size orof larger size to form a stable uniform mix avoiding segregation.Another aspect of fourth embodiment is the introduction of the particlesinto bulk fluid.

When a potent therapeutic agent is used in a mix, the amount oftherapeutic agent used is small and to ensure a uniform mix it isnecessary to increase the number of therapeutic agent particles persample or dose. To do this it is necessary to use a smaller therapeuticagent particle size, however, producing such very fine powder isdifficult and often attended by severe aggregation (using conventionalmilling, spray drying or crystallisation techniques) thus defeating theobject of size reduction in the mixing process. When the proportion oftherapeutic agent is extremely small and finally presented in a smalldose unit, physical dry mixing of solids will fail to produce anadequate dispersion of therapeutic agent within the formulation. Toavoid the above drawbacks, the fourth embodiment of the currentinvention adopts an efficient and reproducible strategy in which thetherapeutic agent is maintained in a liquid. The resulting therapeuticagent-liquid mix is reduced in size by atomisation to form a fine mist.This fine mist contains individual liquid droplets whose size is muchsmaller than that obtainable by conventional milling such asmicronisation and spray-drying. Furthermore these liquid droplets areuniform in size and therapeutic agent content. Using the rightatomisation protocols, the size of the liquid droplets can be arrangedto be several orders of magnitude smaller than that of carrier particlewith which it is mixed. Mixing of the liquid droplets and carrierresults in an efficient, uniform and stable mix. The therapeutic agentadhered to the particle is uniformly distributed and smaller in sizethan the carrier. The therapeutic agent particles can consequentlytravel with the low density engineered carrier, of the third embodiment,to the deep lung. The small size of the therapeutic agent particleenables fast dissolution and transport in lung epithelia. Hence, theproblems of adhesion and cohesion encountered in traditional dry powderinhalers is of no consequence with this invention which is in directcontradiction to the current state of the art.

Advantageously, one or more agents (one or more of which may betherapeutic), carried in a liquid or vapour-loaded state can betransferred to the particle. This liquid state, vapour-loaded state andtransferred agent corrects surface defects, restructures the surface ofthe particles which in turn reduces the cohesiveness of the particles,alters the particle density, particle size and thus their lowproperties. The transferred agent is uniformly distributed to theparticles forming a stable and homogeneous mix. The preferredvapour-loaded states for small quantities of agent transfer includemist, droplets, foam, spray, steam, fog or vapour. The vapour-loadedtransferred state is more efficient and effective than conventionalmethods of mixing dry micronised powders.

Further the particles adhered to the carrier can be present on thecarrier as discrete, discontinuous or continuous particles or films.Apart from transferring agent particles to the carrier, the method oftransfer using the current invention can be manipulated to also changeat least one or combinations of one or more morphological, chemical orphysical features of the particle and/or, transferred agent accordingthe embodiments of this invention. In addition the change of at leastone or combinations of one or more morphological, chemical or physicalfeatures of the particle can be manipulated to occur before, during orafter the transfer of the agent.

Beclomethasone Dipropionate and Fluticasone propionate are examples oftwo highly potent therapeutic agents that are used in extremely lowdoses. Example 11 details the adoption of the fourth embodiment of thisinvention to transfer beclomethasone dipropionate from a vapour loadedstate to spray dried lactose.

From FIG. 20 it is clear that discrete particles of beclomethasone aredeposited on the lactose particles, further, the lactose particles havehairs, have increased surface area, are porous whilst the originalparticle size is maintained. Further-more the size of the discreteattached beclomethasone dipropionate particles are below twomicrometers. The whole particle formulation (i.e. the lactose particlesplus adhered beclomethasone dipropoinate particles) is far below 5micrometers which makes the engineered particles desirable for deliveryto the lungs.

Using the above method it is possible to transfer an agent to a particle(host particle) so that the agent forms discrete discontinuousparticles, alternatively, the same technique can be used to attachcontinuous agent particles over the surface of the host particle or evenform continuous or discontinuous multilayers. To achieve the latter along treatment time is required, to alleviate this problems the secondaspect of the fourth embodiment is applied.

The application of another aspect of the fourth embodiment is typifiedby FIG. 16 of example 8 in which the host particles are immersed in theliquid fluid that contains the agent(s) to be transferred to the hostparticles. From FIG. 16, it is clear that apart from continuouslycovering the host particle with the transferred agent, the resultingparticles have also been architectured to form hairs. Further, thearchitectured particles have increased in size whilst remainingspheroidal.

It should be obvious to those skilled in the art that more than oneagent can be transferred to the host particle and one of such agentstransferred may be a constituent of the host particle (see below).

Transfer of an agent (that is a constituent of the host particle) to thehost particle using the method of this invention is desirable in that itis safe, fast, economical, controls the shape and the size of theparticle whilst repairing surface and crystallographic defects with theoption of architecturing (for example forming hairs, pores, hollowvolume) in one step. Surface and crystallographic defects such as sitesof high energy are reduced, clefts and crevices are filled with thetransferred agent and surface irregularities are smoothed, whilstensuring the content of the host particle is unchanged. High energysites, clefts, crevices and surface irregularities are known to be thecauses of adhesion, cohesion and frictional forces that are the maincauses of poor drug delivery to the lung.

The above process is exemplified by example 16, in which lactose wascarried in a vapour loaded state and deposited onto microfine lactose.

Accordingly, lactose particles used in conventional dry powder inhalerscan be treated by this aspect of the fourth embodiment to decrease thecohesion and adhesion problems normally associated with conventionallactose and especially inhalation grade lactose, other carrier materialsuch as sorbitol, mannitol and the like and also drug particles.

Mass transfer has been done with beclomethasone fluticasone and lactosethe former two are water insoluble whereas the latter is water soluble.Hence the mass transfer technique of this fourth embodiment isapplicable to water soluble and water insoluble agents to formcontinuous (fluticasone) and discrete particulates (beclomethasone).

The fifth embodiment of the present invention provides a method ofcrystallization that not only maintains a spherical shape and highmonodispersity of the particles, but also increases the specific surfacearea of the particles.

Furthermore, it is also clear that hairs are formed on the finalparticles and the size of the final particles show less polydispersitycompared to the starting particles. Since the starting material isglassy and amorphous caused by quench cooling (i.e. extremely rapidcooling) and the final material is crystalline the process of thepresent invention improves the crystallinity of the final product. Theparticles produced by the melt back crystallisation technique has passedthrough at least two changes in states of matter from the frozen stateto the liquid state during treatment back to solid state when the finalparticles are formed (Hence the term MELT-BACK). Thus supporting theclaim for changes in states of matter.

The fifth embodiment of the present invention is the application of themethod of this invention in a so called “melt back” technique thatenables the reduction in the particle size of the starting material byover 1000% if desired without departing from the original shape of thestarting particles, reducing cohesion and optionally architecturing (forexample forming hairs, pores, hollow volume) the particles. In contrastto this embodiment, traditional micronising techniques such as millingand spray drying that produce highly cohesive, amorphous material. Inthis current embodiment the reduction in particle size is coupled withan increase in crystallinity and this is in direct contravention to theteachings of the prior art. Particles produced by the fifth embodimentcan then be architectured using the other embodiments of this invention.

Essentially this embodiment requires the solidification of a particle,preferably by freezing droplets from solutions, melt, suspensions,emulsion, slurry, paste and the like followed by treating the frozen ornon frozen solid particle with a fluid.

The fluid is preferably composed of two miscible mediums containing adissolved agent (such as polymer). The preferable miscible mediums areethanol acetone mixture and the preferable agent is the polymerPolyvinylpyrrolidine alcohol.

The above fluid facilitates melting of the frozen particle into a liquiddroplet and removal of one or more agents of the liquid droplet suchthat the liquid droplet reduces in size thereby concentrating theremaining agents in the liquid droplet to exceed the supersaturationpoint (of the remaining agents in the liquid droplet). This is astarting point from which precipitation or crystallisation proceeds toform a particle whose size is much below that of the starting particle.The final particle is preferably spherical in shape, more preferablyspherical and uniform in size and most preferably spherical, uniform insize and having hairs and/or pores.

The application of the fifth embodiment of this invention is shownExample 7.

In example 7 the starting frozen particles are large (in the order of2-6 mm) yet the final particles are about 30 micrometers, however, usingthe same syringe with a needle attached to the syringe will producestarting particles which are much smaller than 2-6 mm hence the treatedparticle will have a size much smaller than 30 micrometers. For thoseskilled in the art it is clear that techniques for producing very fineliquid droplets, such as atomisation, and such frozen atomised dropletsare much smaller than the starting frozen droplets of the above. In thisinstance nano-sized final particles are envisaged.

EXAMPLES Example 1

The particles to be treated were processed by spray drying. 5 grams (gm)of lactose was dissolved in 100 ml distilled water and the resultingsolution was spray-dried using a Buchi 190 mini-spray dryer according tothe following conditions:

-   Inlet temperature: 176° C.,-   Outlet temperature: 112° C.,-   Aspirator dial reading: 15,-   Feed rate: 5 ml/min,

The resulting particles are shown in FIG. 1:

1 gm spray-dried lactose particles were immersed in a 250 ml flat bottombeaker containing 100 ml of hot ethanol (45° C.) (Absolute, 99.7%, BDH,Poole, U.K) for 10 min to form hairy and porous lactose particles. Thesuspended hairy lactose particles were left to settle and cool for 2 minand were recovered by filtration under vacuum using a Buckner glassfunnel. The resulting particles were recovered in a glass petri dish andallowed to dry in a ventilated oven at 50° C. for 16 hours and theseparticles are shown in FIG. 2:

It will be appreciated that the particles are uniform in size and largercompared to the original spray-dried particles shown in FIG. 1. Comparethis Figure to that of FIG. 2.1 which is that of dandelion fluff whoseattachments are easily dispersed by a slight wind. It is obvious fromFIG. 2 (boxes highlight the detached hairs) that the hairs have detachedfrom the hairy particles (in a similar manner to that of dandelionfluff) and as such it is possible to use the detached hairs alone or incombination. All methods of harvesting the particles using anyseparation methods known, to those skilled in the art, are embodiedwithin this invention.

Compare FIG. 2 to that of FIG. 2.1; which is a picture of the fruitinghead of dandelion fluff. It is clear that there are many similaritiesbetween the two. The particles in both are light in density, fluffy andeasily carried by and follow the direction of the air-stream. Both havepappus-like projections (hairs), these pappi are easily detachable by ahint of air change and follow the direction of the wind. Both are alsospherical. The preparation method was designed to ensure that particlesin FIG. 2 are hollow inside which gives them excellent aerodynamicproperties making them ideal candidates for inhalation.

The particles of FIG. 2 are hairy and microporous, however, they havetendency to aggregate as shown in FIG. 3.

An additional step, such as, ultrasonication was useful inde-aggregating the agglomerated particles before filtration. From thisit is understood, to those skilled in the art, that any de-agglomeratingmethods to obtain partially or fully de-aggregated particles can be usedand are thus embodied within the spirit of this invention. Example 2 isanother de-aggregating method, however, in this case the de-aggregationoccurs before treatment.

Example 2

Pretreatment of 10 gm of the original spray-dried lactose (FIG. 1)contained in a rotating metal bowl with ballotoni beads was used toinitiate primary hair formation and de-aggregate spray-dried particles.The treating fluid ethanol was introduced as an extremely fine mist tothe powder using an air jet nebuliser running at 1 ml/min. 10 ml oftreating fluid was nebulised and treated with the powder on successivesequential occasions (total of 50 ml). Intermittent heat by means ofhair dryer oriented to the back of rotating bowl was also applied. Afterevery 20 ml of the nebulised treating fluid, hot air was applied for 30seconds by mean of hair dryer whose airjet was directed to the back ofthe rotating bowl. This treatment initiated changes in the particlemorphological features including nano-hairs and dimple formation(similar to that of a golf ball), which are obvious from FIG. 4 as wellas de-aggregating the original spray-dried particles (FIG. 1).

Following pre-treatment, the recovered particles (FIG. 4) were immersedand covered with boiling ethanol for 10 seconds to promote rapid hairformation and morphological changes without destroying the originalshape of the particles. These morphological changes include hairs,pores, surface texture, increase in particle size, hollow volume, hairsize, pore size, surface area, crystallinity and the like, as well asimproved particles flow properties. FIG. 5 shows an example of theparticles produced.

It is obvious to those skilled in the art that the particles can besubject to any number of pre-treatments which may include immersion in amedium or subjection to a vapour or any other state of matter and thesepre-treatments can be performed in any sequence to obtain particles withother morphological features of which hairs, dimples, pores and the likeare included. Further treatments or exposure to vapour can formparticles with modified morphological features or enhance themorphological features as shown in the following examples.

The above approach provides an increase in particle size withoutdeparting from the original shape, coupled with the presence of hairs onthe particle surface and pores. It is evident that there was also anincrease in the hollow volume. The particles are composed of 100% of onecomponent (lactose).

Example 3

5 gm of spray-dried lactose (prepared according to example 1) weretreated with 150 ml boiling ethanol contained in a 600 ml flat-bottomedbeaker for 60 seconds. The treated particles were recovered byfiltration and dried as described in example 1. The resulting particleswere stored in a desiccator over silica gel (as desiccant) and theresulting particles are shown in FIG. 6:

FIG. 6 shows hairy and porous lactose particles. These particles havegrown in size to about 20 micrometers. Hence there is also an increasein hollow volume. The particles in FIG. 6 present more extensive hairand pore formation compared to those of FIG. 5 suggesting that if thetreatment temperature is lower then the treatment time must be greaterto obtain a more extensive change in particle morphology. To thoseskilled in the art both time and temperature need to be manipulated toobtain the desired particle morphology which includes the particle size,surface texture, hairs, pores, hollow volume, cystallinity, particleshape, polymorphic form, surface area, flow properties and the like.

A further example to exemplify this statement is FIG. 7 in which 10 gmspray-dried lactose was immersed in ethanol at ambient temperature for45 minutes. It is clear that the particles have increased in size to atleast 70 micrometers and even though hair projections are formed, themorphology of the hairs and particles are radically different from thatof FIGS. 2, 5 and 6. The particles of FIG. 7 may represent the extremeend of hair formation in that the spherical particles lose their shapeand tend to form individual single crystals. This is another method ofobtaining uniform individual pure crystal without the need ofcrystallisation from solution, the latter tends to produce crystals ofnon-uniform size and shape distribution coupled with crystal damagecaused by mechanical stirring for example. The particles of FIG. 7 arebetter able to stabilize the mix due to their extensive projectionsallowing greater contact area. Such particles can be used to efficientlyentrap small drug particles preventing drug detachment during vibration,shipping or handling, thus maintaining a stable uniform mix compared tosmooth particles. These projections will also enable de-aggregation inthe inhaler device allowing better aerosolisation and dispersion of theparticles.

The microbiological analysis of the powders obtained from examples 2 and3 showed no sign of microbiological contamination. Further, the fluidused (ethanol) is known, from the literature, to have preservative,antiseptic and disinfection properties. Further-more, heated ethanol itknown to have sterilization properties.

Example 4

10 gm of spray-dried lactose prepared in a manner similar to example 1were introduced in a rotating bowl containing ballotoni beads. Thetreatment fluid ethanol was introduced as an extremely fine mist to thepowder using an air jet nebuliser running at 1 ml/min. 10 ml oftreatment fluid was nebulised and treated with the powder on successivesequential occasions (total of 160 ml). Intermittent heat by means of ahair dryer oriented to the back of rotating bowl was also applied. Afterevery 20 ml of the nebulised treatment fluid, hot air was applied for 30seconds by means of a hair dryer whose airjet was directed to the backof the rotating bowl.

FIGS. 8 a, 8 b and 8 c indicate the changes in particle morphology asincreasing amounts of treatment mist were used to architecture theparticles.

It is clear from the above Figure that surface texture changes occurwith the treatment medium coupled with heat. These changes in thesurface texture are seen as surface dimpling and nano-projections.

It is also clear from this figure that longer exposure time to thetreatment mist and heat increased the changes in particle morphologysuch as increased surface roughness, dimpling and projections comparedto that of FIG. 8 b

It was clear that treatment with vapour is a long process and thusinefficient, advantageously, it does not affect the starting particlesize whilst enabling architecturing of the particle surface morphology.Vapour treatment can thus be used for partial particle architecturing orto initiate the particle morphological characteristics so that rapidarchitecturing can take place in a more efficient manner as obtainedwith immersion of particles in a liquid. FIG. 9 is a scanning electronmicrograph of fully architectured lactose particles immersed in hotethanol from the starting partially architectured particles as shown inFIG. 8 c. The nano-sized hairs of FIG. 8 c are grown to micron sizehairs of FIG. 9 enabling the operator to control hair size.

Treating with vapour has been shown to improve the flow properties of apowder (example 14) without affecting the particle size. In this presentexample it is possible not only to architecture the particle whilstmaintaining its original particle size it can also be applied toarchitecturing the particle whilst causing very small or massive changesin the particle size and hairs.

This can be achieved, in the current example, by altering 1) treatmentwith vapour and applying heat simultaneously, 2) treatment with thevapour first then applying heat at each successive atomization, 3)atomizing the vapour on many successive occasions then applying heat or4) heating the powder then atomizing the vapour onto the powder. Theresults suggest that scheme 3 produced much greater changes in particlesize, particle morphology and powder properties in a shorter time periodcompared to the rest. However, the resultant particles can then beimmersed in a liquid medium to achieve complete, efficient and uniformarchitecturing

Example 5

The following example, wherein, the agents (polyvinyl alcohol andlactose) are both insoluble in the treatment medium.

0.1 gm of Polyvinyl alcohol (PVA, 10,000 MW) was dissolved in 100 ml ofdistilled water at 70° C., once dissolved 5 gm of lactose was dissolvedin the PVA solution. The resulting solution was allowed to cool andspray-dried according to the conditions in example 1.1 gm of spray-driedlactose-PVA shown in FIG. 10 was treated with 150 ml boiling ethanol for30 seconds to form hairy particles as shown in FIG. 11.

Once again, the treated particles are hairy, with many projections andthe particles have increased in size.

FIG. 11.1 is a photomicrograph of spray-dried lactose-PVA particlesimmersed in hot ethanol for 60 seconds.

Longer exposure produces fluffy candyfloss like particles. Moreextensive hair projections compared to FIG. 11 after a total exposuretime of 60 seconds. This example shows that the time of exposure and thetemperature of the treatment fluid influence hair architecture. Toexemplify the different ways of architecturing hairs compare FIG. 2,FIG. 5, FIG. 6, FIG. 7, FIG. 15 and FIG. 16.

Example 6

The following example, wherein, the agent (PVP 24000 MW) is soluble inthe treatment medium, whereas the agent (lactose) is not soluble in thetreatment medium.

0.025 gm of PVP was dissolved in 100 ml distilled water, 5 gm lactosewas dissolved in the PVP solution. The resulting solution wasspray-dried according to the procedure detailed in example 1. Thespray-dried lactose-PVP particles are shown in FIG. 12. 2 gm ofspray-dried lactose-PVP particles were immersed in 150 ml of boilingethanol for 60 seconds to give particles shown in FIG. 13.

It can be seen that the treated spray-dried lactose-PVP particles stillretain their spherical shape, increased in diameter and presentedconsiderable quantities of hairs after conttreatmentacting with ethanolmedium.

In the two previous examples PVA and PVP were used one is insoluble,whereas, the other was soluble in the treatment fluid. It is clear thatthese excipients changed the nature and texture of the hairs and of theparticle. So it is possible for the operator to use any agent, treatmentfluid or combinations thereof that give particles and hairs of therequired nature and texture. The agent(s) can be soluble or insoluble inthe treatment fluid.

It is claimed that using this technology, the particle size can becontrolled. The previous examples above (example 1 to example 6) showedthat particle size could be manipulated to give required particle size.This was achieved by manipulating the operating conditions such as theadditives, agent(s), treatment fluid or their combinations. The othermorphological features of the particles can be controlled in a similarway to the manner in which the particle size is controlled. For examplethe polymorphic form of lactose can be controlled by coordinating theuse of additives (heat in this example) and treatment fluid to ensurethat lactose remained as α-lactose, β-lactose and combinations thereof.

Extension of these principles (including the co-ordination of agents andadditives) enables the operator to control the polymorphic form of theagent(s). Since the particles in some of the above examples increased insize, their density was reduced, their hollow volume was increased,their surface area increased, their dissolution rate increased, theparticle flow and aerodynamic properties improved. These are someexamples, which are not exhaustive, of the way the operator canco-ordinate and manipulate the operating conditions to achieve therequired particle characteristics.

Example 7

In the detailed description solid frozen particles (or frozen droplets)can be architectured by the melt-back procedure, this is an example ofthis process.

10 gm of lactose was dissolved in 100 ml of distilled water and 20 ml ofthis solution was introduced drop wise, using a 20 ml syringe, intoliquid nitrogen to freeze the droplets. The frozen particles (as shownin FIG. 14) were recovered and introduced in 50 ml of an ethanol/acetonemixture (30/130 v/v) containing 0.025 gm of PVP 24,000 under stirringusing Heidolph 4-blade stirrer at 500 rev/min in a 600 ml beaker atambient temperature. The solvent turned cloudy upon addition of thefrozen lactose droplets, however, stirring was continued for 5 minutes.The resulting particles were recovered by filtration, under vacuum. Theparticles were dried in a ventilated oven at 50° C. for 16 h and storedover silica gel. The particles are shown in FIG. 14.1.

The particles shown in FIG. 14.1 are individual with no signs ofagglomeration and the particles are also uniform in size.

The particles of FIG. 14.1 are hairy porous lactose particles. Suchparticle architecturing is produced by treating the particles with anagent not present in the particles and also treating in a fluid withmore than one medium, whilst mechanically stirring the mixture(additive).

The particles are uniform in size which is about 20 micrometers. Smallerparticles were obtained using smaller bore syringes or atomizing using ajet nebuliser, air brush, spray gun, spay nozzle and the like.

The particles are spherical as that of the original droplet, the hairsare radically different from that presented in the preceding figures. Inthis case the hairs are much thicker and extend from the centre of theparticle (FIG. 15).

These hairs present themselves as stiff crystalline plate-like blades(FIG. 15.1) compared to the fluffy, and light needled shaped hairs ofFIG. 2 and the light, needle like hairs of FIG. 7 and the fluffy, lightand candy floss like hairs of FIG. 11.1. In essence this inventionallows the user to design the hairs required for the purpose.Furthermore, the hairs can be designed, for example, to be deformable,as shown in FIG. 11.1 and or brittle (as shown in FIG. 15.1). It isunderstood that these properties are desirable in the pharmaceuticalarea, for example in inhalation and tabletting as described in thepharmaceutical literature.

In this example as the particle form from the frozen droplet, they areconcurrently architectured to form hairs and it is thus an example ofarchitecturing whilst the particle if forming.

Example 8

A solution of 0.25% w/v of fluticasone in ethanol was prepared by adding0.25 gm of fluticasone to 100 ml of ethanol in a 600 ml round, flatbottomed flask. The mixture was stirred at 500 rpm at 25° C. until thesolution became clear. 10 gm of sprayed-dried lactose, preparedaccording to the conditions of example 1, was added to the resultingsolution The suspension was maintained at a temp of 25° C. and stirredat 500 rpm for 5 minutes using a Heidolph 4 -blade stirrer, which wassituated approximately 1 cm above the bottom of the flask. Thesuspension was filtered and dried according to the conditions in example1.

It is clear that hairs are formed and the particles have increased insize (to about 20 micrometers) but still retain their spherical shape.This experiment is an example of treating the particle with a fluid inwhich one of the constituents of the fluid is not present as aconstituent of the particle. A bi-layer particle is produced and thecoating constituent can act to entrap and retain the activity or protectthe base particle from atmospheric effects such as moisture. Extendingthis technique it is possible to create multi-layer particles whoseconstituents may or may not be biologically-active. This representsanother coating technique, distinct from the traditional methods ofcoating. In this example a solution is used into which the particles areimmersed, equally, the particles may be immersed into a suspension,dispersion, emulsion or the like.

Example 9

It was claimed that it is possible to architecture the particles as manytimes as required to obtain particles of the required morphologicalfeatures. This is an example of this process. 20 gm ofvapour-architectured powder according to example 4 was furtherarchitectured using 140 ml of ethanol (as a fluid) according to theatomisation protocols of example 4:

The powder was placed in a rotating metal bowl. 10 ml of the fluid wasatomised through a nebuliser fitted with a glass connecting tube hangingover the powder bed. During treatment the powder was continuously mixed.After nebulising 10 ml of the fluid, the rotating bowl was heated usinga hair drier to evaporate all the fluid. The above process was repeateduntil the allocated fluid volume had been used. The resulting particleswere spread onto a flat drying tray, which was placed in an oven at atemperature of 50° C. for 16 hours. The resulting particles were placedin a desiccator over silica gel.

From FIG. 17 it is clear that there has been an increase in the extentof hair formation, compared to FIGS. 8 b and 8 c, and still thespherical shape whilst the particle size was shifted slightly to theright i.e. a slight increase in particle size (FIG. 25.2). Hence themethod of the current invention can shift the whole particle sizedistribution. It is also clear that increasing the amount of fluidatomized to the particles slowly increases the particle size whilsttreating the particles with liquid fluid causes much greater and morerapid changes in particle size and particle features. As a result it maybe concluded that treatment of the particles with a vapour is lessaggressive than treating the particles with a liquid at equivalenttreatment conditions. Apart from the hairs obtained a specificmorphological feature, such as the pores in this case, was manipulatedin a way so as to increase the extent and number of pores. Thesecharacteristics are important in the pharmaceutical andnon-pharmaceutical fields. An example in the pharmaceutical field,porous particles have been shown to improve drug delivery to the lungdue to their favourable aerodynamic properties (Large porous particlesfor sustained protection from Carbachol-induced bronchoconstriction inguinea pigs, Abdellaziz Ben-Jebria, et al, Pharm. Res. 16(4):555-561,1999). Porous particle have desirable properties in that they imparthigh specific surface area to the powder and thus facilitate improveddissolution rate. In food and cosmetics industries, the porous nature ofthe particle will retain perfumes, flavourants, fragrances, clothesconditioners, opacifiers, deodorants or any other entrappableconstituents for longer periods of time. These particles will maintainand release menthol taste (in smokers tooth paste, chewing gums,gargles), perfume, deodorant effect, release of antiseptics, and releaseof anti-lice materials to pet coats over a longer time period. In foodindustry, these particles can be used to entrap multiple flavourants,colourants and fragrances in one particle. These porous and hairyparticles are also useful for household products, car industry,pesticides and fertilizer, husbandry industries, tobacco industry, waterpurification and medical industries

It is possible for the operator to modify or enhance a particularfeature of the particle in modifying the operating conditions.

Example 10

In example 9 the constituents of the particle were insoluble in thefluid, however, in this example the constituents of the particle aresoluble in the fluid. Using the same experimental conditions as theexample 9, above, the powder from example 9 was furthervapour-architectured using 100 ml of a 94/6% ratio of ethanol/water (asthe fluid).

It is clear that the use of ethanol/water mixture as a fluiddramatically changes the surface morphology and extent of hairformation. It is possible to choose a pure fluid or a fluid mix thatwill give the operator particles with the required morphology. It wasshown previously that liquid architecturing at elevated temperaturesincreased the size of the particles. These particles of increased sizecould then be recovered and vapour-architectured either with pure fluid,fluid mixes or combinations thereof to achieve the required surface andmorphological attributes.

In example 9 and example 10 the size, type, nature and number of thepores were manipulated by altering the operating conditions. From FIG.18 the pores where much larger and different in shape to that of FIG.17. The importance of the number, shape and size of the pores are thatmore ingredients (such as flavourants, colourants and drugs) can beincorporated within these particles and their release profiles fromthese particles can be modified.

Example 11

Trofast, 1992 (Patent WO 92/18110) used pure anti-solvent vapour,whilst, Trofast, 1995 (Patent WO 95/05805) used pure solvent oranti-solvent vapour to condition a powder in order to make it morestable. This example shows the transfer of a therapeutic agent(beclomethasone (BDP)) onto lactose/PVP particles while architecturingthe particles. In this example beclomethasone (BDP) was dissolved inethanol. The resulting solution was nebulised and used to architecturelactose/PVP particles.

Lactose/PVP spray-dried particles were prepared by dissolving 0.025 g ofPVP (24,000 molecular weight) in 100 ml deionised water, to this PVPsolution 11.7 gm of lactose was dissolved and the resulting solution wasspray-dried using a Buchi spray dryer according to experimentalconditions given in example 1.

The spray-dried lactose particles in the presence of PVP are shown inFIG. 19.

It is clear from FIG. 19 that the particles are smooth and spherical inshape.

These spray-dried lactose/PVP particles were treated with ethanol vapourcontaining BDP. The experimental conditions are as follow:

10 mg BDP was dissolved in 50 ml ethanol, the resulting solution wastreated with 5 gm of spray-dried particles using an air jet nebuliserrunning at 1 ml/min. Atomisation was carried out at room temperature.After atomisation the particles were dried at room temperature. Theresulting particles are shown in FIG. 20.

The boxed areas on FIG. 20 show the even distribution of BDP particleson the lactose-PVP base particles. PVP was used in this example, as itis known from the previous examples, that it extensively forms hairs inthe presence of ethanol. Lactose also forms hairs in the presence ofethanol but to a lesser extent than PVP. Hence the presence of PVP willmaximize hair formation whilst minimizing the time of treatment with thefluid, which in this case is ethanol. This example uses two excipients,one of which is soluble (PVP) in the fluid (ethanol), whilst the other(lactose) is insoluble in the fluid (ethanol). The ethanol in the fluidhas multiple functionalities, one of which is that it architectures PVPand lactose to form hairs. Secondly, it acts as a carrier for thetransfer of an agent (BDP) and to deposit that agent onto the surface ofthe particles. Ethanol was chosen as it is safe (compared to othersolvents), it has high volatility hence it rapidly evaporates leavingthe therapeutic agent on the surface of the particle. This shows thatthe process and materials used are flexibly used to achieve the desiredproperties for the intended application.

It is obvious from FIG. 20 that the deposited BDP are of suitable sizefor inhalation purposes. This technology has great applicability inother areas, for brevity, and such example is in tablet formationtechnology. In tabletting technology it is well known that optimaltablets are obtained when plastically deforming and fragmentingmaterials are compacted together. The plastically deforming andfragmenting material are usually prepared as a physical mixture, to thisphysical mixture the drug is added before tabletting. However, in thisinstance a uniform formulation cannot be assured and de-mixing andsegregation always occurs. The particles of the present invention can besuccessfully used in tabletting as the plastically deforming PVP,fragmenting lactose and drug are incorporated into one particle,assuring formulation uniformity hence better compressibility thanphysical mixtures, minimizing the processing time, minimizing the costcompared to labour and cost intensive wet and dry granulation techniquesroutinely used in tablet technology.

It is known that if a potent drug is used in a mix, the amount of drugused is small and to ensure a uniform mix it is necessary to increasethe number of drug particles per sample or dose. To do this it isnecessary to use a smaller drug particle size, however, producing suchvery fine powder is difficult and often attended by severe aggregationthus defeating the object of size reduction in the mixing process. Whenthe proportion of active (in this case beclomethasone) is extremelysmall and finally presented in a small dose unit, physical dry mixing ofsolids will fail to produce an adequate dispersion of drug within theformulation. To avoid the above drawbacks, the current invention adoptsan efficient and reproducible strategy in which the drug is dissolved inethanol to form a perfect mix. This perfect mix is reduced in size byatomization from an air-jet nebuliser to form a fine mist. This finemist contains individual liquid droplets whose size is much smaller thanthat obtainable by conventional milling. Further more these liquiddroplets are uniform in size, size distribution and drug content. Hencemixing is carried out by treating lactose-PVP particles contained in arotating tumbling chamber with atomized liquid droplets. Evaporation ofthe solvent leaves beclomethasone particles adhered to the surface ofthe lactose particles. The fine mist surrounds the tumbling lactose-PVPparticles resulting in uniform beclomethasone particles on the surfaceof each lactose-PVP particle (FIG. 20). The solvent also acts as anarchitecturing agent, in architecturing the lactose and depositedbeclomethasone to form particles with desired morphological features,which stabilise the mix hence preventing segregation whilst improvingthe flow properties of the formulation. This process is rapid andachieves different objectives in one step. These objectives may be;particle size reduction; uniform mixing, architecturing; enhancing thepowder flow properties. A suspension, emulsion and the like of the drugcan be treated in a similar fashion as discussed above and any particleand any treatment fluid can be used.

Example 12

Surprisingly, the transfer of agents to the particle (as shown inexamples 8 and 11) reduced inter-particulate cohesion and improved theflow of the powder. In both examples, the agent transferred were notpart of the particle (hence a bi-constituent particle is obtained) andthe transferred agents were hydrophobic. Equally it is also desirable toobtain mono-component particles with low cohesion that produces a powderthat flows well. In this example the transferred agent is theconstituent agent of the particle (in this case lactose) thus forming amono-component particle, also this transferred agent is alsohydrophilic.

10 gm of lactose was added and dissolved in 100 ml of distilled water. 6ml of the resulting solution was added to 94 ml of ethanol. 50 ml ofthis resultant liquid was atomized onto 10 gm of spray-dried lactose(prepared according to example 1) using the atomization protocolsdescribed in example 4.

From FIG. 21 it is clear that hairs are formed and the particles areporous and flow tests demonstrated a dramatic improvement in powder flowproperties. The mist can also be formed from lactose suspension,emulsion or the like. Pre-treated particles and untreated particles (asshown in example 16) can also be used instead of spray-dried particlesin fact particles from any source can be used. Spray-dried lactose wasused in this example as spray dried particles are spherical in shape andthis spherical shape is a desired property. The processes of thisinvention have shown that despite the improvement in the powderproperties, the original spherical shape was maintained through out.Hence, particles of other shapes can be treated by this inventionwithout altering the shape whilst dramatically improving the particlesproperties.

Example 13

Microfine lactose (BDI) as directly obtained from the supplier wastreated in three ways;

1) A 100 gm sample was retained in a 45 micrometer mesh size sieve andexposed to liquid nitrogen vapour for about 5 minutes. The resultingpowder was spread onto a flat tray and placed, to dry, in a ventilatedoven at 50° C. The resulting powder was then stored in a desiccatorabove silica gel until used.

2) Another 100 gm sample was thinly spread onto a flat stainless steeltray (dimensions 30 cm×23 cm×1.5 cm) and sufficient liquid nitrogen waspoured onto the powder to immerse all the powder. The liquid nitrogenwas allowed to evaporate at room temperature. To prevent anycondensation, the resulting powder was transferred and thinly spreadonto another tray of equal dimensions. This latter tray was placed, todry the powder, in a ventilated oven at 50° C. The resulting powder wasthen stored in a desiccator above silica gel until used.

3) Another 100 gm sample was treated with liquid nitrogen vapour asdescribed in example 1) above, immediately after exposure to liquidnitrogen vapour, the powder immersed into liquid nitrogen. Again theliquid nitrogen was allowed to evaporate and the resulting powder wastransferred and thinly spread onto tray (of the dimensions to thatdescribed in 2 above). This latter tray was placed, to dry the powder,in a ventilated oven at 50° C. The resulting powder was then stored in adesiccator above silica gel until used.

All three treatments produced less cohesive and free flowing powdercompared to the starting microfine powder. Surprisingly, there was nosign of adhesion of particles to glass containers, in which thesetreated powders were stored, was observed unlike the untreated powderwhich aggressively adhered to the glass container wall

The particle size distribution of Microfine lactose and the samples ofMicrofine lactose prepared according to the above three treatments weredetermined with a Sympatec Helos Particle Size Analyzer at twodispersion pressures (1 and 3 bar). The results of the analyses areshown from FIGS. 22.2-22.8.

From FIGS. 22.1 to 22.8, at 1 Bar dispersion pressure, untreatedMicrofine lactose exhibits a broad size distribution with a significantshoulder this shoulder was more apparent using a high dispersionpressure (3 bar). The change in the particle size distribution ofuntreated Microfine lactose with increased dispersion pressure suggeststhe presence of substantial particle aggregates, that require highpressure for their de-aggregation and dispersion (See FIG. 24). Whereas,in contrast, All Microfine samples treated with liquid Nitrogen eitheras a vapour, a liquid or combinations thereof improved and normalisedthe particle size distribution without affecting the particle size. Fromthe above, a preferred treatment is using the vapour of liquid nitrogen,a more preferred treatment is with liquid nitrogen and the mostpreferred treatment is with combinations of liquid nitrogen and thevapour of liquid nitrogen. Further, comparing FIGS. 22.4 and 22.8, thereis no difference in the particle size distribution even though thedispersion pressure is reduced from 3 bar to 1 bar. This observation isextremely advantageous for dry powder inhalations powders as a lowinhalation flow rate is sufficient to disperse particles treated in thismanner

Furthermore, this treatment method, in contrast to the prior art, isapplicable to water soluble, water insoluble, thermolabile and fragilematerials (such as proteins peptides and genes). The method is patientand envornmentally friendly and is easily scalable at minimal costs.

Liquid nitrogen was used for this example, those skilled in the art areaware that other liquefied gases, refrigerants, anaesthetics and otherlow temperature liquids can be used.

Example 14

The flow properties of the powder was measured by the angle of reposeusing the poured method (as described by Wells, J. I., Pharmaceuticalpreformulation, Ellis Horwood, Chichester, 1988) Material Angle ofrepose (θ) Spray dried lactose DOES NOT FLOW (FIG. 1, from Example 1)Liquid vapour 28 (FIG. 8c, from Example 4) introduced to the lactoseparticles Lactose particles 19.15 (FIG. 6, from Example 3) added to theliquid fluid

According to the literature, the lower the angle of repose the betterthe flowability of the powder and powders with angle of repose less than30 have good flow, whereas, values below 25 indicate excellentflowability. Thus engineered particles have superior flow propertiescompared to that of the starting material.

Example 15

Deposition/Aerodynamic Testing of Engineered and Lactose Crystals

Apparatus:

A modified twin stage impinger apparatus (mTSI) developed for this study(assessing aerodynamic properties of the engineered and non-engineeredlactose particles) was based on the standard glass twin stage impinger(Apparatus A of the British Pharmacopeia, BP 2001) (FIG. 23.1). It wasemployed with a view to deposit lactose and a mixture of lactoses(engineered hairy, engineered porous and non-engineered lactose) ontothe adhesive tape placed on an aluminium stub of SEM.

The air jet filter at the lower stage of the standard TSI was removedfrom the coupling tube and replaced by the microscope stub which wasattached to the base of the conical flask by means of blu-tak. A smallgap was left between the microscope stub and the coupling tube to enableair flow through the mTSI. 7 ml of distilled water was introduced intothe upper chamber of mTSI whilst the lower chamber remained liquid free.Blend were prepared of the following

-   50 mg spray dried lactose (From example 1, FIG. 1.), 50 mg of hairy    lactose (From example 1., FIG. 2) and 50 mg

A glass device with a 29 Quickfit® socket was fitted to the glass throatof the mTSI. to aerosolize 150 mg of hairy lactose particles (of Example0.1 and FIG. 2) at 60 L/min. This experiment was performed in triplicateusing the same flow rate i.e 60 L/min. After each deposition of hairyparticles, the mTSI was dismantled and the stub removed from the lowerstage flask. The mTSI parts were thoroughly washed and dried betweendepositions and resultant stubs were viewed using a scanning electronmicroscope.

From FIG. 23.3 it is evident that engineered hairy lactose particles aslarge as 60 micrometers deposit in the lower stage of the twin stageimpinger. Yet the twin stage impinger at a flow rate of 60 L/min isquoted to have a cut of diameter of between 6.3 to 6.4 micrometer, hencethe hairy engineered lactose particles of the present invention musthave good aerodynamic properties. Further, from FIGS. 23.3 and 23.4,hairs have detached from the hairy particle during particle flight andupon impact with the stub. Furthermore the brittle nature engineered tothe hairy lactose particles have resulted in wholesale fragmentation ofhairy lactose particles upon impact with the stub spreading thefragments over a large surface area. The presence of engineered hairylactose particles on the lower stage of the twin stage impinger suggestthat they have a longer time of flight than conventional lactoseparticles of similar size that are designed to remain in the device ordeposit in the upper stage of the twin stage impinger.

Example 16

0.125 gm of lactose was dissolved in 100 ml of distilled water. 7.5 mlof this lactose solution was added to 292.5 ml of ethanol (purity 99.7%absolute ethanol). The resulting solution was the treatment fluid thatwas atomized onto microfine lactose, as obtained from the manufacturer.

300 gm of microfine lactose (BDI, U.K) was placed in the bowl of adomestic Platinium Pro Breville mixer. The fluid was introduced as anextremely fine mist to the powder using an air jet nebuliser running at1 ml/min. 10 ml of fluid was nebulised and used to treat the powder onsuccessive sequential occasions (total of 220 ml). During atomization ofthe fluid the surface of the particles in contact with the fluid wascontinuously renewed. After every 20 ml of the nebulised fluid, hot airwas applied for 30 seconds by mean of hair dryer whose airjet wasdirected to the side of the rotating bowl.

The final powder was spread thinly onto a stainless steel tray andplaced in an oven maintained at a temperature of 50° C. and the powderallowed to dry for 48 hours. FIG. 0.24. shows the resulting cones formedfrom the drained method (Aulton, M. E., Pharmaceutics The Science ofDosage form design, Second edition, 2002, page 205).

The amount of lactose carried in the vapour loaded state was chosen tobe small so as not to deviate the particle size from that of thestarting material. FIG. 24 compares the cones formed, using the drainedmethod, of the untreated microfine lactose and treated microfinelactose. The heap formed by the untreated microfine lactose does notresemble that of a cone (which is should if it has good flow properties)and it exhibits clumped agglomerates that are indicative of cohesionbetween the particles. Whereas the treated microfine lactose forms adefined smooth heap with no agglomeration or clumps suggesting areduction in cohesion and consequent improvement in powder flow.

Example 17

Blend Homogeneity Lactose and Beclomethasone

Measurement of dose uniformity of Beclomethasone Dipropionate from theblend prepared by transferring beclomethasone dipropionate from a vapourloaded state to spray dried lactose.

The homogeneity of the blend was examined by analysing the quantity ofBDP in aliquots (400.4±2 mg) of sampled powder, each aliquot of blendwas placed in a 100 ml volumetric flask and made up to the volume withHPLC mobile phase (acetonitrile: water in the ratio 70 :30, v/v) and theamount BDP was determined by HPLC (Shimadzu, Japan) using UV detectionat 239 nanometers. Ten aliquots were taken randomly from the blend andthe resulting solution from each aliquot was assayed in duplicate. Theco-efficient of variation (% cv) was used to assess the homogeneity ofthe blend. The percentage recovery was found to 98.4±2.4 correspondingto a % cv of 2.43. The results suggest a uniform mix was achieved usingthe mixing procedure described in this embodiment

Example 18

The particle size distribution of Spray-dried lactose (FIG. 1,Example 1) and the vapour architectured spray dried lactose (Example 9,FIG. 17) determined with a Sympatec Helos Particle Size Analyzer at 1Bar dispersion pressure. The results of the analyses are shown below.

Note that there was an increase in the volume mean diameter (VMD) from2.69 μm (for spray-dried before ethanol vapour architecturing) to 7.61μm (after ethanol vapour architecturing). The particle size distributionhas also been shifted towards larger size after treatment with ethanolvapour from example 9.

1-33. (canceled)
 34. A particle, having at least one changedmorphological, chemical or physical feature, wherein said changedfeature can facilitate the attachment of at least one agent to the outersurface of the particle, thus permitting the particle to act as acarrier for said at least one agent; wherein one changed feature is anincreased hollow volume.
 35. A particle according to claim 34 whereinthe one or more further changed features are selected from the groupconsisting of hairs, pores, surface dimpling, spongy-like formation,modified particle surface roughness, particle shape, particle size,density, modified specific surface area, reducing cohesiveness, improvedpowder flow, improvement in aerodynamic properties of the particle,transfer and attachment of at least one agent to the particle, theresult of transfer of at least one agent, and combinations thereof. 36.A particle according to claim 34 wherein the particle is spherical inshape.
 37. A particle according to claim 34 wherein the particle isbetween 0.05 μm and 4000 μm in diameter.
 38. A particle according toclaim 34 wherein the agent is selected from the group consisting oftherapeutic agents, prophylactic agents, diagnostic agents, excipients,diluents, flavorants, fragrances, dyes, nutrients, and sweeteners.
 39. Aparticle according to claim 34 wherein the agent is a therapeutic agentselected from the group consisting of corticosteroids,anti-inflammatories, antitussives, bronchodilators, diuretics,anticholinergics, hormones, analgesics, vaginal preparations,antiallergics, anti-infectives, antihistamines, anti-neoplastic agents,anti-tuberculosis agents, proteins, polymeric drugs, lipids, organicsubstances, inorganic substances, nutrients, pro-drugs, antigenspeptides, and derivatives thereof.
 40. A particle according to claim 34wherein the particle is administered by a route selected from the groupconsisting of pulmonary, oral, parental, nasal, rectal, tonsillar,buccal, intra-ocular, topical/transdermal, and vaginal administration.41. A particle according to claim 34 wherein the agent is selected fromthe group consisting of beclomethasone, fluticasone, lactose, polyvinylpyrrolidone, and polyvinyl alcohol.
 42. A particle according to claim 34wherein the particle itself acts as an agent.
 43. A method of treatingparticles to engineer/architecture the particles with particularchemical, morphological and physical features or combinations thereof,wherein one such feature is an increased hollow volume, said methodcomprising the steps of optionally processing, at least one agent toform a particle; treating the particle by making available a fluid,alone or in combination with at least one additive(s) or furtheragent(s), to the particle to promote change in one or more of themorphological, chemical or physical features of the particle; repeatingstep (b) as many times as necessary; harvesting engineered particles;and repeating steps (a) to (d) as many times as necessary.
 44. Themethod of claim 43 wherein a further engineered/architectured feature isthe formation of hairs on the surface of the treated particle.
 45. Amethod according to claim 43 wherein the promoted change of step (b)results in at least one further change to the particle, and wherein thefurther change is selected from the group consisting of forming and orpromoting and or controlling the growth of hairs; modifying theproperties of the existing hairs; promoting the formation of pores;modifying the properties of existing pores; modifying the density,modifying and controlling the particle size, controlling particle sizegrowth, increasing or decreasing the surface area or specific surfacearea of the particle; reducing the cohesiveness of the particles;increasing the flow of the powder; forming and/or modifying surfacedimpling; formation and/or modification of sponge-like formations;alteration of particle surface roughness, improvement in the aerodynamicproperties of the particle, ability of the particles to form a stableuniform mix, and ability of the particles to improve blend uniformityand content uniformity.
 46. A method according to claim 43 wherein atleast one further agent(s), further fluid(s), further additive(s) orcombination thereof, is added to any of stages a) to e).
 47. A methodaccording to claim 43 wherein the agent is selected from the groupconsisting of corticosteroids, anti-inflammatories, antitussives,bronchodilators, diuretics, anticholinergics, hormones, analgesics,vaginal preparations, antiallergics, anti-infectives, antihistamines,anti-neoplastic agents, anti-tuberculosis agents, proteins, polymericdrugs, lipids, organic substances, inorganic substances, nutrients,pro-drugs, antigens peptides and derivatives, and combinations thereof.48. A method according to claim 43 wherein the agent(s) of the particleis either a combination of polyvinyl alcohol and lactose, a combinationof polyvinylpyrolidone and lactose or lactose.
 49. A method according toclaim 43 wherein the additive is selected from the group consisting ofheat, moisture, radiation, pressure, shear forces, magnetic forces,vibration, stirring, vortexing, vacuum, mixing, tumbling, centrifuging,masticating, ultra-sound waves or extruding, electrical, deaggregationagents, and combinations thereof.
 50. A method according to claim 43wherein at least one selected additive is stirring.
 51. A methodaccording to claim 43 wherein at least one selected additive is themaintenance of the heat range −200 to 200° C.
 52. A method according toclaim 43 wherein the engineering step lasts for between 1 microsecondand several hours.
 53. A method according to claim 43 wherein the agentof the particle or agent added to the particle during the engineeringprocess is a polymer.
 54. A method according to claim 53 wherein thepolymer is selected from the group consisting of polyvinyl alcohol,polyvinylpyrolidone and polyethylene glycols.
 55. A method according toclaim 43 wherein the fluid contains at least one medium, and/or at leastone agent, and/or at least one additive and combinations thereof, thatpromotes changes in any of the morphological, chemical or physicalfeatures of the particle.
 56. A method according to claim 43 wherein thefluid is in the bulk liquid state, dispersed liquid state, vapor stateor combinations thereof and is either aqueous, organic, liquefied gasesor a combination thereof.
 57. A method according to claim 56 wherein theliquid state is selected from the group consisting of droplets, mist,fog, and spray.
 58. A method according to claim 43 wherein the fluid isselected from the group consisting of water, hydrocarbon liquids,halogenated hydrocarbons, mineral spirit, mineral oils, mineral acids,oxygenated solvents, alcohols, nitrogen containing hydrocarbons, sulfurcontaining hydrocarbons, hetero-atom containing hydrocarbons,anesthetics, liquefied gases such as liquid nitrogen, the vapor fromliquid nitrogen or combinations thereof, and refrigerants.
 59. A methodaccording to claim 43 wherein the fluid is selected from the groupconsisting of water, acetone, ethanol, and combinations thereof.
 60. Amethod according to claim 43 wherein engineering the particle with fluidcomprises introducing the fluid, which may be static or in motion, tothe particle either in bulk, as droplets, as a foam, as a mist, as fogor as a spray.
 61. A method according to claim 43 wherein engineeringthe particle with fluid comprises introducing the particle, which may bein static or in motion, to the fluid either in bulk, as dispersedparticles, as droplets, as a foam, as a mist, as fog or as a spray. 62.A method according to claim 43 wherein the further agent added ispolyvinylpyrrolidone, lactose or therapeutic agents such asbeclomethasone dipropionate or fluticasone propionate.
 63. A low densitydrug carrier particle having hairs on the surface thereof, wherein theparticle acts as a carrier for the delivery of either anti-inflammatorydrugs, bronchodilator drugs or a combinations thereof into the lungs ofa patient via dry powder inhalation.
 64. A carrier particle according toclaim 63 wherein the drugs being delivered are selected from the groupconsisting of beclomethasone dipropionate, fluticasone propionate,salbutamol sulfate, and a combination thereof.